ScienceWeek

SCIENCEWEEK

ScienceWeek
January 17, 2003
Vol. 7 Number 3

An Online Digest of Research in the Sciences

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There must be no barriers to freedom of inquiry.
There is no place for dogma in science. The scientist
is free, and must be free to ask any question, to
doubt any assertion, to seek for any evidence,
to correct any error.
-- J. Robert Oppenheimer (1904-1967)

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Section 1

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Thematic Issue: Evolutionary Developmental Biology

1. Introduction.
2. On the Conceptual Framework of Evolutionary Developmental
Biology.
3. Development and Evolution: Theoretical Aspects.
4. Epigenetics: Genes, Differentiation, and Development.
5. Organ Development.
6. Gut Formation in Animals.
7. Body Patterning in Development.
8. On the Development of the Brain.

Notices and Subscription Information

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Section 2

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1. Introduction.

From the Editor: The emerging new field of evolutionary
developmental biology represents a coalescence of research in
evolution and embryology that is causing considerable excitement
among many biologists, especially those aspects that involve
molecular genetics. A major interest is in identifying and
studying the genes that help transform a single-celled egg into a
multicellular adult. Researchers have recently made extraordinary
progress in characterizing such genes, finding in some cases that
the same gene sequences in different species may trigger
different developmental processes, and that in other cases genes
and groups of genes may be used as modules in the development of
widely varying biological forms. Researchers in this new field
are convinced their studies will eventually have an enormous
impact on evolutionary theory. There is apparently already a
major shift underway in the attitudes of evolutionary and
developmental biologists toward each other, with changes in the
names of major journals, inclusions of chapters on evolutionary
biology in embryology textbooks and vice versa, and so on. The
growth of "evo-devo" signifies an apparent sea-change in two
classical realms of biology, and most researchers feel that great
insights are just beyond the near horizon.

ON DEVELOPMENTAL MECHANISMS OF EVOLUTIONARY CHANGE.

"When Wilhelm Roux [1850-1924] announced the creation of
experimental embryology in 1894, he broke many of the ties that
linked embryology to evolutionary biology. According to Roux,
embryology was to leave the seashore and forest and go into the
laboratory. However, he promised that embryology would someday
return to evolutionary biology, bringing with it new knowledge of
how animals were generated and how evolutionary changes might
occur. He stated that 'an ontogenetic and a phylogenetic
developmental mechanics are to be perfected.' Roux thought that
research into the developmental mechanics of individual embryos
(the ontogenetic branch) would proceed faster than the
phylogenetic (evolutionary) branch, but he predicted that 'in
consequence of the intimate causal connections between the two,
many of the conclusions drawn from the investigation of
individual development [would] throw light on the phylogenetic
processes.' A century later, we are now at the point of
fulfilling Roux's prophecy and returning developmental biology to
questions of evolution. This return is producing a new model of
evolution that integrates both developmental genetics and
population genetics.

"The fundamental principle of this new evolutionary synthesis is
that evolution is caused by heritable changes in the development
of organisms. This view can be traced back to [Charles] Darwin
[1809-1882], and it is compatible with and complementary to the
view of evolution based on population genetics that evolution is
caused by changes in gene frequency between generations. The
merging of the developmental genetic approach to evolution ('evo-
devo') with the population genetic approach is creating a more
complete evolutionary biology that is beginning to explain the
origin of both species and higher taxa...

"Developmental biology brings to evolutionary biology, first, a
new understanding about the relationships between genotypes and
phenotypes, and second, a new understanding about the close
genetic relationships between organisms as diverse as flies and
frogs. In doing so, developmental biology complements the
population genetics approach to evolutionary biology. It also
highlights new questions. For instance, there can now be a
population genetic approach to the regulatory genes. One can also
look at how paracrine factors, signal transduction pathways, and
transcription factors have changed during the evolution of
various phyla. Evolutionary developmental biology can also
provide answers to classic evolutionary genetics questions such
as these posed by mimicry and industrial melanism. The genes
involved in these processes are being identified so the
mechanisms of these phenomena can be explained. To explain
evolution, both the population genetics and the developmental
genetics accounts are required."

Scott F. Gilbert: Developmental Biology, 6th Edition, Sinauer
Associates 2000, pp.679,705.

ON DEVELOPMENTAL CONSTRAINTS.

"A discussion (J.M. Smith et al: Quart. Rev. Biol. 1985 60:265)
of developmental constraints by nine authors resulted in the
following definition: 'A developmental constraint is a bias on
the production of variant phenotypes or a limitation on
phenotypic variability caused by the structure, character,
composition, or dynamics of the developmental system.' The idea
is that different groups of living things evolved distinct
developmental mechanisms, and that the way an organism develops
will influence the kinds of mutation it is likely to generate. A
plant, for example, may be likely to mutate to a new form with
more branches than would a vertebrate, because it is easier to
produce that kind of change in the development of a plant
(indeed, it is not even clear what a new 'branch' would mean in
the vertebrate -- perhaps it might be extra legs, or having two
heads). The rates of different kinds of mutation -- or of
'production of variant phenotypes' in the quoted definition --
therefore differs between plants and vertebrates.

"Developmental constraints can arise for a number of reasons.
Pleiotropy is an example. A gene may influence the phenotype of
more than one part of the body. A trivial instance would be that
genes influencing the length of the left leg probably also
influence the length of the right leg. The growth of legs
probably takes place through a growth mechanism controlling both
legs. This mechanism does not have to be inevitable for a
constraint to exist. Perhaps some rare mutants do affect the
length of only the right leg. A developmental constraint exists
whenever there is a tendency for mutants (in this example) to
affect both legs, and the tendency is due to the action of some
developmental mechanism.

"Pleiotropy exists because a one-to-one relation is not present
between the parts of an organism that a gene influences and the
parts of an organism that we recognize as characters. The genes
divide up the body in a different way from the human observer.
Genes influence developmental processes, and a change in
development will often change more than one part of the
phenotype. Much the same reasoning lies behind a second sort of
developmental constraint. New mutations often disrupt the
development of the organism. A new mutant, with an advantageous
effect, may also disrupt other parts of the phenotype. The
disruptions will probably be disadvantageous, but if the mutant
has a net positive effect on fitness, natural selection will
favor it. In some cases, the disruption can be measured by the
degree of asymmetry in the form of the organism. In a species
with bilateral symmetry, for example, any deviation from
bilateral symmetry in an organism is a measure of how well
regulated its development was. Mutations can, therefore, cause
developmental asymmetry."

Mark Ridley: Evolution, 2nd Edition. Blackwell Science 1996,
p.353.

ON HOMEOBOX GENES

"In the 1980s, the door to incorporating developmental insights
into evolutionary theory was finally opened with the discovery of
a class of highly conserved regulatory genes, called homeobox
genes. Homeobox genes control an organism's development by means
of sending signals from one to another in the form of the
proteins they produce. As demonstrated in the fruit fly, the cell
that eventually gives rise to the egg cell receives the messages
that determine what will be the head and tail and up, down,
right, and left sides of a potential offspring by a back-and-
forth signaling, carried by proteins, between homeobox genes in
this cell and the cells of the ovary around it. The animal that
then emerges from the egg that derives from this predetermined,
pre-egg cell obtains its specific features through the process of
turning on and off certain homeobox genes at different times in
different regions of its developing body. All animals, from
unsegmented worms to fruit flies, starfish, tunicates, zebra
fish, chickens, mice, and humans, share essentially the same
basic homeobox genes. Since all of an organism's genes are
contained in each and every one of its cells, the striking
morphological difference between animals lies basically in which
cells and when during development one or more homeobox genes are
active... It is mind-boggling to realize that, for all intents
and purposes, many differences between a fruit fly and a human
may lie pretty much in where and when certain homeobox genes are
activated. To be sure, there are some other differences between a
fruit fly and a human at the molecular level. But, fundamentally,
the main difference between organisms lies in alterations in
development that result from differences in the timing of
homeobox gene activity."

Jeffrey H. Schwartz: Sudden Origins: Fossils, Genes, and the
Emergence of Species. John Wiley & Sons 1999, p.12

ON EVOLUTIONARY BIOLOGY AND THE STUDY OF INSECTS

"A great number of studies aimed at understanding the evolution
of development have been carried out within insects. Without a
doubt, this is largely because our detailed understanding of the
genetic and molecular basis of pattern formation in the model
insect, Drosophila melanogaster, provides an excellent starting
point for a large number of comparative studies. In addition,
insects are an evolutionary diverse group of animals; almost one
million species of insects have been described, and estimates of
insect diversity place the total number of undescribed insect
species at over 20 million. More importantly, there is an
enormous range of morphological and developmental diversity found
within this group of animals, extending from spectacularly
colored butterflies, to stick insects, to horned beetles, to
wingless silverfish, to minuscule parasitic wasps. Over the last
few years, evolutionary studies within the insects have ranged
from characterizing the genetic and molecular changes responsible
for reproductive isolation between closely related species of
Drosophila, to comparing gene expression patterns to understand
the developmental basis for variation in appendage number among
differently related members of this group. A number of
investigations have also focused on the evolution of the
developmental process of segmentation. Finally, recent studies in
a variety of insects have revealed interesting molecular changes
in the process of axis formation... It is particularly important
that researchers continue to take advantage of as many different
groups of insects as possible; this is the only way we can
adequately address the evolutionary questions facing us."

Nipam H. Patel: Proc. Nat. Acad. Sci. 2000 97:4442

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2. ON THE CONCEPTUAL FRAMEWORK OF EVOLUTIONARY DEVELOPMENTAL
BIOLOGY.

Wallace Arthur (University of Sunderland, UK) discusses
evolutionary developmental biology, the author making the
following points:

1) Evolutionary developmental biology has its origins in the
comparative embryology of the nineteenth century, and in
particular in the work of Karl von Baer (1792-1876)(1) and Ernst
Haeckel (1834-1919)(2,3), whose "laws" were put forward as being
generally applicable to the way in which development evolves,
regardless of the taxon concerned. Following a quiescent period
of almost a century, present-day evo-devo erupted out of the
discovery of the homeobox genes in the early 1980s(4,5). One
principal focus over the last 20 years has been the comparative
study of the spatiotemporal expression patterns of developmental
genes, both homeobox-containing (hence coding for transcription
factors) and others. Although there are many cases of
conservation of expression patterns, there are also cases where
these patterns differ markedly between closely related species,
even when the gene concerned acts at a very early developmental
stage.

2) We have thus moved from one extreme to the other: from laws
that turn out to be, at best, overgeneralizations, to a situation
where it almost seems that anything goes, that is, any
developmental gene, its expression pattern and the resultant
ontogenetic trajectory, can evolve in any way. If this were true,
no generalizations would be possible, let alone universally
applicable laws. However, the search for general patterns is
fundamental to science and is not easily suppressed, even when
the relevant data-set looks very complex, as it currently does in
evolutionary developmental biology. There are signs, particularly
over the last few years, that new general concepts are emerging.

3) What is the current status of the laws of von Baer and
Haeckel? One view is that Haeckel's recapitulation was wrong but
von Baer's embryonic divergence essentially right; however, it
can be argued that the pattern that is observed depends on the
type of comparison being made. For comparisons among animals of
the same level of phenotypic complexity, such as different
vertebrate classes, von baerian divergence may be the norm.
However, when comparisons are made between very different levels
of complexity, the pattern that emerges is broadly
recapitulatory, although only in a very imprecise way, in the
sense of recapitulating levels of complexity rather than precise
morphological details. So, taking a broad view, both von Baer and
Haeckel captured elements of the truth: evolution leads both to
embryonic divergence and, in some lineages, to a lengthening of
the ontogenetic trajectory leading to more complex adult
phenotypes with greater numbers of cells, their embryos passing
through simpler, quasi-ancestral forms. There is, however, an
important restriction to this general model. Von Baer's
divergence applies only after the "phylotypic" stage. Earlier
development is interspecifically variable, converging to this
point of maximum similarity, and only after that diverging again.
This "egg-timer" or "hourglass" model of development11 renders
the situation messier, but should not lead us to abandon the idea
of von baerian divergence altogether, especially as the hourglass
is a very asymmetric one, with the point of constriction close to
the beginning.

4) In summary: Over the last twenty years, there has been rapid
growth of a new approach to understanding the evolution of
organismic form. This evolutionary developmental biology, or
"evo-devo", is focused on the developmental genetic machinery
that lies behind embryological phenotypes, which were all that
could be studied in the past. Are there any general concepts
emerging from this new approach, and if so, how do they impact on
the conceptual structure of traditional evolutionary biology? In
providing answers to these questions, the author assesses whether
evo-devo is merely filling in some missing details, or whether it
will cause a large-scale change in our thinking about the
evolutionary process.

References (abridged):

1. Von Baer, K. E. Uber Entwicklungsgeschichte der Tiere:
Beobachtung und Reflexion (Borntr„ger, K”nigsberg, 1828).

2. Haeckel, E. Generelle Morphologie der Organismen (Georg
Reimer, Berlin, 1866).

3. Haeckel, E. The Evolution of Man: a Popular Exposition of the
Principal Points of Human Ontogeny and Phylogeny (Appleton, New
York, 1896).

4. Scott, M. P. & Weiner, A. J. Structural relationships among
genes that control development: sequence homology between the
Antennapedia, Ultrabithorax and fushi tarazu loci of Drosophila.
Proc. Natl Acad. Sci. USA 81, 4115-4119 (1984).

5. McGinnis, W., Garber, R. L., Wirz, J., Kuroiwa, A. & Gehring,
W. J. A homologous protein-coding sequence in Drosophila homeotic
genes and its conservation in other metazoans. Cell 37, 403-408
(1984).

Nature 2002 415:757

Related Background Brief:

THE CONCEPT OF DEVELOPMENTAL REPROGRAMMING AND THE QUEST FOR AN
INCLUSIVE THEORY OF EVOLUTIONARY MECHANISMS. Evolutionary
developmental biology has already made a major contribution to
our understanding of evolutionary patterns, notably homology.
However, while it has the potential to make an equally important
contribution to our understanding of evolutionary mechanisms, and
indeed to the integration of mechanism and pattern, it has not
yet done so. The author explores how this potential may be
realized. In particular, the author focus on the limitations of
present-day neo-Darwinian theory, and indicate how a combination
of the neo-Darwinian and "evo-devo" approaches provides a more
inclusive view of evolutionary mechanisms with greater
explanatory power. There is a particular focus on developmental
reprogramming, which lies logically between mutation and
selection, yet has been neglected in mainstream evolutionary
theory. The inclusion of developmental reprogramming in the list
of evolutionary mechanisms leads to a view that the direction of
evolutionary change is determined by a combination of internal
and external factors, rather than being controlled entirely by
the environment. W. Arthur: Evol Dev 2000 2:49.

Related Background:

EVOLUTIONARY DEVELOPMENTAL BIOLOGY: FUTURE PROSPECTS

The various fields of science are conceptual categorizations,
constructions of the human mind, and as such are continually in
flux in response to new data and new ways of looking at old data.
At the beginning of the 20th century, the fields of evolutionary
biology and embryology were in an intellectual partnership, each
field invigorated by data and ideas of the other field. Then, in
the 1920s, evolutionary biology embraced the new science of
genetics and began a conceptual drift away from embryology and
embryological concepts. Embryology, in turn, came to rename
itself "developmental biology", and remained relatively distant
from evolutionary biology in ideas and methods for half a
century. Only in the 1980s did a second conjunction of these two
important biological disciplines begin.

Peter W.H. Holland (University of Reading, UK) presents an
analysis of the new interface called "evolutionary developmental
biology", the author making the following points:

1) The past 15 years have seen a reconciliation between
evolutionary biology and developmental biology, with the new
discipline of evolutionary developmental biology emerging at the
interface. This new discipline is concerned with a) how
developmental processes have evolved; b) how developmental
processes can be modified by genetic change; and c) how such
modifications produced the past and present diversity of
morphologies and body plans.

2) Three main factors have contributed to the recent emergence
and phenomenal growth of evolutionary developmental biology, all
three factors dependent on genetics -- the discipline that split
evolution and development apart 60 years earlier. The three
factors are as follows:

... ... a) The first and perhaps major factor was the discovery
that animals as different as *nematodes, flies, and mammals use
similar genes for similar developmental purposes, such as
controlling the development of spatial organization in the
embryo. The author suggests that "we can now state with
confidence that most animal phyla possess essentially the same
genes, and that some (but not all) of these genes change their
developmental roles infrequently in evolution."

... ... b) The second crucial factor was the rise of molecular
phylogenetics -- the comparison of nucleic acid sequences from
different organisms and the construction of evolutionary trees
from these data.

... ... c) The third factor was the set of technological advances
in molecular biology (e.g., the *polymerase chain reaction)
invented or refined in the 1980s, and which facilitated the
*cloning and analysis of genes in any species, not just the
handful of model species traditionally studied.

3) The author points out that the link between the genetic make-
up of an organism (its "genotype") and its form and function (its
"phenotype") lies at the heart of evolutionary developmental
biology. In the coming decades, a fundamental question to be
addressed is how alterations to the genotype as a result of
mutation are transformed through the intermediary of development
into changes in form. Another question in need of resolution
concerns the importance of gene duplication in the evolution of
development. Are there developmental processes that are possible
with two copies of a gene but not with one copy? At present, this
is a controversial idea, since it implies that gene number could
impose tight genetic constraints on evolution.

4) Concerning the conjunction of developmental biology and the
study of fossils and the evolutionary relationships and ecologies
of organisms which formed these relationships (i.e., the field of
paleontology), the authors points out that 15 years ago few
developmental biologists would have heard of the *Ediacaran
fauna, and few paleontologists would have admitted an interest in
*Drosophila genetics. Much has changed: paleontologists and
developmental biologists are now regularly combining data to
tackle key questions in evolutionary developmental biology.
Paleontology is vital to estimating when a particular
evolutionary change occurred, and paleontology can also reveal
whether such a change was correlated with other evolutionary
events or with environmental change. The "*Cambrian explosion" of
animal phyla is the classic example, but its interpretation
remains controversial. Paleontology clearly records a rapid
increase in the abundance and diversity of animal fossils at the
base of the Cambrian period, but there is disagreement as to
whether this increase reflects increases in body size, the origin
of shells and skeletons, or a true rapid diversification of body
plans. Even if the last explanation is accepted, did this burst
of evolution occur in the ancestors of all multicellular animals,
or only among the lineages exhibiting bilateral symmetry
(bilaterians)?

Nature 1999 402supp:C41

Text Notes:

... ... *nematodes: An abundant and ubiquitous phylum of
unsegmented roundworms.

... ... *polymerase chain reaction: (PCR): A technique for
isolating and amplifying any specifically desired DNA sequence.
PCR is considered by many molecular biologists to be the most
important technical advance in molecular biology in the second
half of the 20th century. The inventor of the technique, Kary
Mullis, received the Nobel Prize in Chemistry in 1993 for his
discovery.

... ... *cloning: The term "cloning" has several meanings which
depend on context. With reference to DNA (the present context),
cloning is any process by which a gene or fragment of DNA is
spliced into a *vector so that the DNA can be amplified many
times by transferring the recombinant (i.e., foreign) DNA
molecule into a host organism (usually a bacterium or yeast) that
can be grown in large quantities.

... ... *vector: In this context, a vector is any DNA that can
propagate itself rapidly in a host cell and maintain this
capability after insertion of foreign DNA into the vector. For
example, one can introduce a human DNA fragment (e.g., a gene)
into the DNA of a virus, have this virus infect its usual host
cells (e.g., bacteria or animal cells), and if the virus is
rapidly replicating, the fragment of human DNA will also be
rapidly replicated. The procedure, in other words, uses viral DNA
as a means (a vector) to introduce the foreign DNA (here a human
DNA fragment incorporated into the viral DNA) into a host cell to
use the host cell-virus system as a chemical factory to produce
relatively large quantities of the foreign DNA fragment.

... ... *Ediacaran fauna: The term "Ediacaran" refers to an
assemblage (until recently the oldest) of soft-bodied marine
animals, the assemblage first discovered in the Ediacara Hills in
Australia. Although the recent discoveries of Ediacaran metazoans
have extended the record of sponges and bilateral animals to 570
million years ago, the biological affinities of many Ediacaran
organisms remains controversial.

... ... *Drosophila: A fruit fly genus, the organism widely used
in 20th century genetics and developmental biology.

... ... *Cambrian explosion: The geological period known as the
Cambrian is the time frame from about 505 million years ago to
545 million years ago. Its most outstanding aspect is the rather
sudden appearance of numerous invertebrate fossils, so numerous
that some have termed it an explosion of evolutionary processes.

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3. DEVELOPMENT AND EVOLUTION: THEORETICAL ASPECTS.

Greg Gibson (North Carolina State University, US) discusses
development and evolution, the author making the following
points:

1) In the context of development, a process is "robust" if it can
proceed normally despite the enormous capacity for perturbation
inherent in all biological systems.

2) Theoretical quantitative genetics, one of the most successful
of all fields of biological enquiry, seems to have run into
somewhat of a dead end when it comes to the integration of
development and evolution. Robustness and the dynamics of
development are two particularly fundamental problems that have
proven difficult to approach with classical methods [1] . There
are signs though that fresh ideas [2,3] and fresh empirical
approaches [4] are opening up a productive new research program
that may see tighter interaction between mathematical and
experimental biology.

3) The developmental problem essentially boils down to the fact
that static statistical models cannot capture the full complexity
of dynamic interactions between genes and the environment.
Quantitative geneticists like to study the relationship between
genetic polymorphism and phenotypic variation. Genotypes are
constants, and phenotypes are captured at a single point in time,
usually well after all of the interesting developmental processes
have concluded. The null hypothesis is no association, and
departures are fit initially as additive contributions and then,
if necessary, dominance and interaction terms are introduced. For
those not accustomed to quantitative genetic reasoning -- namely,
most molecular and cellular biologists -- the arcane algebra can
seem distant and irrelevant. Development, after all, is assumed
to be complex and dominated by interactions due to phenomena such
as redundancy, feedback and synergism. How do we reconcile these
world views?

4) One place where it may be productive to integrate them is in
terms of our understanding of "robustness", or developmental and
physiological stability. Robustness is gaining increasing
attention as the flip side of diversification, and as a process
at the heart of disease processes from psychological disturbance
to diabetes to aging in general. The incredible observation is
that, despite the fact that it takes 20,000 genes to make a
complex multicellular organism, and that these have to work
together in environments as diverse as the jungles of Mauritius
or suburban Detroit, development works. Arms and legs are the
same length in each individual, livers and hearts are the
appropriate size, and the brain wires itself correctly, all in
the face of considerable potential for perturbation.

References (abridged):

1. Zhivotovsky L.A. and Feldman M.W. (1992) On models of
quantitative genetic variability: a stabilizing selection-balance
model. Genetics, 130:947-955.

2. von Dassow G., Meir E., Munro E. and Odell G.M. (2000) The
segment polarity network is a robust developmental module.
Nature, 406:188-192.

3. Meir, E., von Dassow, G., Munro, E. and Odell, G.M. (2002).
Robustness, flexibility, and the role of lateral inhibition in
the neurogenic network. Curr. Biol. 2002 12:778

4. Houchmanzadeh B., Wieschaus E. and Leibler S. (2002)
Establishment of developmental precision and proportions in the
early Drosophila embryo. Nature, 415:798-802.

Current Biology 2002 12:R347

Related Background Brief:

THERE IS NO HIGHLY CONSERVED EMBRYONIC STAGE IN THE VERTEBRATES:
IMPLICATIONS FOR CURRENT THEORIES OF EVOLUTION AND DEVELOPMENT.
Embryos of different species of vertebrate share a common
organization and often look similar. Adult differences among
species become more apparent through divergence at later stages.
Some authors have suggested that members of most or all
vertebrate clades pass through a virtually identical, conserved
stage. This idea was promoted by Haeckel, and has recently been
revived in the context of claims regarding the universality of
developmental mechanisms. Thus embryonic resemblance at the
tailbud stage has been linked with a conserved pattern of
developmental gene expression -- the "zootype". Haeckel's
drawings of the external morphology of various vertebrates remain
the most comprehensive comparative data purporting to show a
conserved stage. However, their accuracy has been questioned and
only a narrow range of species was illustrated. In view of the
current widespread interest in evolutionary developmental
biology, and especially in the conservation of developmental
mechanisms, re-examination of the extent of variation in
vertebrate embryos is long overdue. The authors present the first
review of the external morphology of tailbud embryos, illustrated
with original specimens from a wide range of vertebrate groups.
The authors find that embryos at the tailbud stage -- thought to
correspond to a conserved stage -- show variations in form due to
allometry, heterochrony, and differences in body plan and somite
number. These variations foreshadow important differences in
adult body form. Contrary to recent claims that all vertebrate
embryos pass through a stage when they are the same size, the
authors find a greater than 10-fold variation in greatest length
at the tailbud stage. The authors suggest their survey seriously
undermines the credibility of Haeckel's drawings, which depict
not a conserved stage for vertebrates, but a stylized amniote
embryo. In fact, the taxonomic level of greatest resemblance
among vertebrate embryos is below the subphylum. The wide
variation in morphology among vertebrate embryos is difficult to
reconcile with the idea of a phyogenetically-conserved tailbud
stage, and suggests that at least some developmental mechanisms
are not highly constrained by the zootype. The authors suggest
their study also highlights the dangers of drawing general
conclusions about vertebrate development from studies of gene
expression in a small number of laboratory species. M.K.
Richardson et al: Anat Embryol (Berl) 1997 196:91.

Related Background Brief:

COMPARATIVE DEVELOPMENT OF ANURANS: USING PHYLOGENY TO UNDERSTAND
ONTOGENY. Hypotheses of relationships are critical to describing
and understanding patterns of evolution within groups of
organisms. But rarely has a comparative, historical approach been
employed to study developmental change, particularly among
anurans. A recent resurgence of interest in collecting basic
ontogenetic information provides us with the opportunity to
compare ontogenetic trajectories in a phylogenetic framework.
Larval skeletons and osteological development were examined for
22 taxa and compared to two hypotheses of relationships -- that
of Cannatella, and one proposed herein based on 41 morphological
characters from larvae and 62 from adults. Larval characters were
mapped on the alternate cladograms using the ACCTRAN optimization
criterion. Several larval features are highly conserved among
some anurans, suggesting that there is some level of canalization
of morphology early in ontogeny. In contrast, a number of
morphologies vary among groups, supporting that there have been
major evolutionary modifications to anuran larval morphologies
early in ontogeny and in the early evolutionary history of
anurans. A.M. Maglia et al: American Zoologist 2001 41:538.

Related Background Brief:

HETEROCHRONY AND HETEROTOPY: STABILITY AND INNOVATION IN THE
EVOLUTION OF FORM. Heterochrony, change in developmental rate and
timing, is widely recognized as an agent of evolutionary change.
Heterotopy, evolutionary change in spatial patterning of
development, is less widely known or understood. Although Haeckel
coined the term as a complement to heterochrony in 1866, few
studies have detected heterotopy or even considered the
possibility that it might play a role in morphological evolution.
The authors review the roles of heterochrony and heterotopy in
evolution and discuss how they can be detected. Heterochrony is
of interest in part because it can produce novelties constrained
along ancestral ontogenies, and hence result in parallelism
between ontogeny and phylogeny. Heterotopy can produce new
morphologies along trajectories different from those that
generated the forms of ancestors. The authors argue that the
study of heterochrony has been bound to an analytical formalism
that virtually precludes the recognition of heterotopy, so the
authors provide a new framework for the construction of
ontogenetic trajectories and illustrate their analysis in a
phylogenetic context. The authors suggest that the study of
development of form needs tools that capture not only rates of
development but the space in which the changes are manifest. The
authors suggest the framework outlined by them provides tools
applicable to both. When appropriate tools are used and the
necessary steps are taken, a more comprehensive interpretation of
evolutionary change in development becomes possible. The authors
suggest there will be very few cases of change solely in
developmental rate and timing or change solely in spatial
patterning, since most ontogenies evolve by changes of
spatiotemporal pattern. M.L. Zelditch and W.L. Fink: Paleobiology
1996 22:241.

Related Background Brief:

BIAS IN THE INTRODUCTION OF VARIATION AS AN ORIENTING FACTOR IN
EVOLUTION. According to New Synthesis doctrine, the direction of
evolution is determined by selection and not by "internal causes"
that act by way of propensities of variation. This doctrine rests
on the theoretical claim that because mutation rates are small in
comparison to selection coefficients, mutation is powerless to
overcome opposing selection. Using a simple population-genetic
model, this claim is shown to depend on assuming the prior
availability of variation, so that mutation may act only as a
"pressure" on the frequencies of existing alleles, and not as the
evolutionary process that introduces novelty. The authors
demonstrate that mutational bias in the introduction of novelty
can strongly influence the course of evolution, even when
mutation rates are small in comparison to selection coefficients.
The authors suggest that recognizing this mode of causation
provides a distinct mechanistic basis for an "internalist"
approach to determining the contribution of mutational and
developmental factors to evolutionary phenomena such as
homoplasy, parallelism, and directionality. L.Y. Yampolsky and A.
Stoltzfus: Evol Dev 2001 3:73.

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4. EPIGENETICS: GENES, DIFFERENTIATION, AND DEVELOPMENT

In general, the term "epigenetics" refers to influences on gene
expression other than those produced by direct changes in the
nucleotides of the genome. In recent years, it has become
increasingly apparent that in living cells complex epigenetic
processes that control gene expression are as important as the
genome code itself in determining cellular biochemistry and
physiology, cell differentiation, and the development of tissues,
organs, and the organism.

M. Azim Surani (University of Cambridge, UK) discusses genes and
differentiation, the author making the following points:

1) Development is a remarkably orderly process, beginning with a
totipotent zygote and ending with an array of specific
differentiated cell types in adults. Approximately 40,000 genes
are needed to build a human being possessing approximately 200
histologically distinct cell types, and these categories can be
subdivided further into a myriad of specialized cell types. These
cells fulfill precise functions that are as diverse as mounting a
defense against diseases, regulating energy input-output, and
building neural networks that allow us to interact with our
environment.

2) Once a cell is fully differentiated, this state is strikingly
stable. Regardless of how different a neuron is from a liver cell
(hepatocyte), most cells retain an intact genome with the full
complement of genes that are present at the beginning in the
zygote. This simple concept of profound significance for
development had its origin in the work of Hans Spemann (1869-
1941). The distinguishing features of cells arise from an orderly
selection of genes that are expressed while the remainder of
genes are switched off.

3) The genetic network that controls developmental decisions is
beginning to be defined. The ability to acquire and inherit gene-
expression patterns efficiently is also crucial to the individual
history of cell differentiation. There are potential mechanisms
that can allow a differentiated cell to perpetuate the "molecular
memory" of the developmental decisions that created it. We know
that this occurs without alterations or deletions of any DNA
sequences, but rather by epigenetic mechanisms that propagate
appropriate patterns of gene expression. These mechanisms involve
heritable but potentially reversible modifications of DNA,
primarily methylation of cytosine-guanine dinucleotide. The
binding of specific protein complexes to DNA also occurs,
resulting in stable and heritable chromatin structures that
ensure efficient silencing of genes that are no longer required
for determination of cell fate -- i.e., allowing expression of
only those genes that define properties of specific
differentiated cell types.

Nature 2001 414:122

Related Background Brief:

RADICAL ALTERATIONS IN THE ROLES OF HOMEOBOX GENES DURING
ECHINODERM EVOLUTION. Echinoderms possess one of the most highly
derived body architectures of all metazoan phyla, with radial
symmetry, a calcitic endoskeleton, and a water vascular system,.
How these dramatic morphological changes evolved has been the
subject of extensive speculation and debate, but remains
unresolved. Because echinoderms are closely related to chordates
and postdate the protostome/deuterostome divergence, they must
have evolved from bilaterally symmetrical ancestors. The authors
report the expression domains in echinoderms of three important
developmental regulatory genes (distal-less, engrailed, and
orthodenticle), all of which encode transcription factors that
contain a homeodomain. The authors suggest their findings
demonstrate that the reorganization of body architecture involved
extensive changes in the deployment and roles of homeobox genes.
These changes include modifications in the symmetry of expression
domains and the evolution of several new developmental roles, as
well as the loss of roles conserved between arthropods and
chordates. Some of these modifications seem to have evolved very
early in the history of echinoderms, whereas others probably
evolved during the subsequent diversification of adult and larval
morphology. These results demonstrate the evolutionary lability
of regulatory genes that are widely viewed as conservative. C.J.
Lowe and G.A. Wray: Nature 1997 389:718.

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5. ON ORGAN DEVELOPMENT.

To an engineer with open eyes, the assemblage of parts that
constitute a living organism is an engineering marvel. The
exterior anatomy of an insect, for example, involves a complex
arrangement of numerous parts with specific mechanical and
sensory functions, and this assemblage is replicated with great
precision in the production of each generation. In an ordinary
manufacturing plant, the various parts of a machine are usually
manufactured independently of each other and then the finished
parts assembled according to an external grand plan to produce
the final manufactured product. In a biological organism,
however, the "manufacturing" scheme is quite different: In the
first place, the "grand plan" is internal and not external: each
cell of the organism carries the "grand plan" -- the genome --
with specific parts of the plan activated in each cell type, and
the activation/inactivation of specific parts of the genome are
differentially dynamic in various cell types during the
developmental process. Secondly, during development of the
embryo, body parts are developed in parallel, in tandem, in
sequence, with an intricate network of control loops, until
finally the complete developed product emerges in toto as a
functioning entity. How is this biological development and
assembly process orchestrated? One of the most spectacular
findings of recent years has been that flies and mice use the
same genes for specifying embryonic developmental regions along
the anterior-posterior axis of the body.

In the embryos of higher animals, there occurs the transformation
of a single-layer "blastula" into a 3-layered "gastrula"
consisting of ectoderm (outermost layer), mesoderm (middle
layer), and endoderm (innermost layer) surrounding a cavity with
one opening. The 3 layers are called the "germ layer", and these
layers, via further cell differentiation and proliferation,
determine the development of all the major body systems and
organs. The term "gastrulation" refers to the process that
transforms the single-layered blastula into the 3-layered
gastrula.

C. Thisse and L.I. Zon (Louis Pasteur University, FR) discuss
organogenesis, the authors making the following points:

1) During the evolution of multicellular organisms, the
homeostatic function of organs provided animals with a selective
advantage. In vertebrates, most of organogenesis occurs during
embryonic development and is often completed before birth or
before hatching. At the onset of organ development, cells in the
embryo are associated with one of three germ layers: the
ectoderm, mesoderm, and endoderm (1). Each organ has its
embryonic origins from one of these layers, although distinct
cell populations from each layer will occasionally mix to form an
organ. For instance, the gastrointestinal epithelium is derived
from endoderm, but the intestine also contains connective tissue
and muscle cells that are derived from mesoderm. This tripartite
segregation of germ layers is associated with the migratory
events of gastrulation and is linked to the spatial and temporal
formation (or patterning) of the embryonic axes. In most
vertebrates, the position of the organs along the dorsal-ventral
axis is conserved. The notochord and muscle are located dorsally,
whereas kidney and blood form in more ventral tissues. The
examination of morphological similarities and differences between
animal phyla has been used historically to develop a basic
understanding of organ development. This comparative approach,
taken together with new molecular and genetic tools, has led to
the reevaluation of classical concepts in the developmental
biology of organ formation.

2) Organs are formed from groups of cells within a developmental
field. The concept of a field implies a homogenous multipotential
stage before differentiation occurs (2-5). Cells within the field
are specified and selected to become a particular type or
lineage. Despite the apparent morphologic homogeneity, molecular
techniques have revealed that cells within a field can express
distinct genes before organ development, a condition called
"prepatterning". Cell lineage commitment within the field can
occur early and quickly. The specified cells within the field
undergo morphogenesis, the process of cell movement and
coalescence as tissues change form. Morphogenesis is guided by
both soluble and cell-associated ligand-receptor interactions.
During or after morphogenesis, organs form into recognizable
units through cell-specific differentiation and proliferation. As
a general rule, the cells of the embryo remain plastic with
respect to cell-specific commitment until late in the process of
organ formation.

3) In summary: Organs are specialized tissues used for enhanced
physiology and environmental adaptation. The cells of the embryo
are genetically programmed to establish organ form and function
through conserved developmental modules. The authors suggest that
the zebrafish is a powerful model system poised to contribute to
our basic understanding of vertebrate organogenesis. The authors
develop the theme of modules and illustrate how zebrafish have
been particularly useful for understanding heart and blood
formation.

References (abridged):

1. R. S. Beddington and J. C. Smith, Curr. Opin. Genet. Dev. 3,
655 (1993).

2. E. M. De Robertis, E. A. Morita, K. W. Cho, Development 112,
669 (1991).

3. J. Huxley, G. de Beer, The Elements of Experimental Embryology
(Cambridge Univ. Press, Cambridge, 1934).

4. L. Wolpert, J. Theor. Biol. 25, 1 (1969).

5. H. Spemann, Roux's Arch. Ent. Mech. 48, 533 (1921).

Science 2002 295:457

Related Background Brief:

THE GENE TINMAN IS REQUIRED FOR SPECIFICATION OF THE HEART AND
VISCERAL MUSCLES IN DROSOPHILA. The homeobox-containing gene
tinman (msh-2, Bodmer et al., 1990 Development 110, 661-669) is
expressed in the mesoderm primordium, and this expression
requires the function of the mesoderm determinant twist. Later in
development, as the first mesodermal subdivisions are occurring,
expression becomes limited to the visceral mesoderm and the
heart. The author demonstrates that the function of tinman is
required for visceral muscle and heart development. Embryos that
are mutant for the tinman gene lack the appearance of visceral
mesoderm and of heart primordia, and the fusion of the anterior
and posterior endoderm is impaired. Even though tinman mutant
embryos do not have a heart or visceral muscles, many of the
somatic body wall muscles appear to develop although abnormally.
When the tinman cDNA is ubiquitously expressed in tinman mutant
embryos, via a heatshock promoter, formation of heart cells and
visceral mesoderm is partially restored. The author suggests that
tinman seems to be one of the earliest genes required for heart
development and the first gene reported for which a crucial
function in the early mesodermal subdivisions has been
implicated. R. Bodmer: Development 1993 118:719.

Related Background Brief:

THE IDENTIFICATION OF GENES WITH UNIQUE AND ESSENTIAL FUNCTIONS
IN THE DEVELOPMENT OF THE ZEBRAFISH, DANIO RERIO. In a large-
scale screen, the authors isolated mutants displaying a specific
visible phenotype in embryos or early larvae of the zebrafish,
Danio rerio. Males were mutagenized with ethylnitrosourea (ENU)
and F2 families of single pair matings between sibling F1 fish,
heterozygous for a mutagenized genome, were raised. Egg lays were
obtained from several crosses between F2 siblings, resulting in
scoring of 3857 mutagenized genomes. F3 progeny were scored at
the second, third and sixth day of development, using a
stereomicroscope. In a subsequent screen, fixed embryos were
analyzed for correct retinotectal projection. A total of 4264
mutants were identified. Two thirds of the mutants displaying
rather general abnormalities were eventually discarded. The
authors kept and characterized 1163 mutants. In complementation
crosses performed between mutants with similar phenotypes, 894
mutants have been assigned to 372 genes. The average allele
frequency is 2.4. The authors identified genes involved in early
development, notochord, brain, spinal cord, somites, muscles,
heart, circulation, blood, skin, fin, eye, otic vesicle, jaw and
branchial arches, pigment pattern, pigment formation, gut, liver,
motility and touch response. The collection of the authors
contains alleles of almost all previously described zebrafish
mutants. From the allele frequencies and other considerations,
the authors estimate that the 372 genes defined by the mutants
probably represent more than half of all genes that could have
been discovered using the criteria of their screen. The authors
provide an overview of the spectrum of mutant phenotypes
obtained, and discuss the limits and the potentials of a genetic
saturation screen in the zebrafish. P. Haffter et al: Development
1996 123:1.

Related Background Brief:

REGULATION IN THE HEART FIELD OF ZEBRAFISH. In many vertebrates,
removal of early embryonic heart precursors can be repaired,
leaving the heart and embryo without visible deficit. One
possibility is that this "regulation" involves a cell fate switch
whereby cells, perhaps in regions surrounding normal progenitors,
are redirected to the heart cell fate. However, the lineage and
spatial relationships between cells that are normal heart
progenitors and those that can assume that role after injury are
not known, nor are their molecular distinctions. The authors
report they have adapted a laser-activated technique to label
single or small patches of cells in the lateral plate mesoderm of
the zebrafish and to track their subsequent lineage. The authors
find that the heart precursor cells are clustered in a region
adjacent to the prechordal plate, just anterior to the notochord
tip. Complete unilateral ablation of all heart precursors with a
laser does not disrupt heart development if performed before the
18-somite stage. By combining extirpation of the heart precursors
with cell labeling, the authors find that cells anterior to the
normal cardiogenic compartments constitute the source of
regulatory cells that compensate for the loss of the progenitors.
One of the earliest embryonic markers of the premyocardial cells
is the divergent homeodomain gene, Nkx2.5. Of interest is that
normal cardiogenic progenitors derive from only the anterior half
of the Nkx2.5-expressing region in the lateral plate mesoderm.
The posterior half, adjacent to the notochord, does not include
cardiac progenitors and the posterior Nkx2.5-expressing cells do
not contribute to the heart, even after ablation of the normal
cardiogenic region. The cells that can acquire a cardiac cell
fate after injury to the normal progenitors also reside near the
prechordal plate, but anterior to the Nkx2.5-expressing domain.
Normally they give rise to head mesenchyme. They share with
cardiac progenitors early expression of GATA 4. The authors
suggest that the location of the different elements of the
cardiac field, and their response to injury, indicates that the
prechordal plate supports and/or the notochord suppresses the
cardiac fate. G.N. Serbedzija et al: Development 1998 125:1095.

Related Background Brief:

CONVERGENCE OF DISTINCT PATHWAYS TO HEART PATTERNING REVEALED BY
THE SMALL MOLECULE CONCENTRAMIDE AND THE MUTATION HEART-AND-SOUL.
One of the earliest steps in heart formation is the generation of
two chambers, as cardiogenic cells deployed in the epithelial
sheet of mesoderm converge to form the nascent heart tube. What
guides this transformation to organotypic form is not known. The
authors report they have identified a small molecule,
concentramide, and a genetic mutation called heart-and-soul (has)
that disrupt heart patterning. Both cause the ventricle to form
within the atrium. The authors demonstrate that the has gene
encodes PKC lambda. The effect of the has mutation is to disrupt
epithelial cell-cell interactions in a broad range of tissues.
Concentramide does not disrupt epithelial interactions, but
rather shifts the converging heart field rostrally. What is
shared between the concentramide and has effects is a reversal of
the order of fusion of the anterior and posterior ends of the
heart field. The authors conclude that the polarity of cardiac
tube assembly is a critical determinant of chamber orientation
and is controlled by at least two distinct molecular pathways.
The authors suggest that combined chemical/genetic dissection can
identify nodal points in development that are of special
importance in understanding the complex patterning events of
organogenesis. R.T. Peterson et al: Current Biology 2001 11:1481.

Related Background Brief:

GRIDLOCK SIGNALING PATHWAY FASHIONS THE FIRST EMBRYONIC ARTERY.
Arteries and veins are morphologically, functionally, and
molecularly very different, but how this distinction is
established during vasculogenesis is unknown. The authors
demonstrate, by lineage tracking in zebrafish embryos, that
angioblast precursors for the trunk artery and vein are spatially
mixed in the lateral posterior mesoderm. Progeny of each
angioblast, however, are restricted to one of the vessels. This
arterial-venous decision is guided by gridlock (grl), an artery-
restricted gene that is expressed in the lateral posterior
mesoderm. Graded reduction of grl expression, by mutation or
morpholino antisense, progressively ablates regions of the
artery, and expands contiguous regions of the vein, preceded by
an increase in expression of the venous marker EphB4 receptor
(ephb4) and diminution of expression of the arterial marker
ephrin-B2 (efnb2). grl is downstream of notch, and interference
with notch signaling, by blocking Su(H), similarly reduces the
artery and increases the vein. Thus, a notch-grl pathway controls
assembly of the first embryonic artery, apparently by
adjudicating an arterial versus venous cell fate decision. T.P.
Zhong et al: Nature 2001 414:216.

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6. ON GUT FORMATION IN ANIMALS

B. Fuss and M. Hoch (University of Bonn, DE) discuss gut
formation, the authors making the following points:

1) The morphological processes involved in the development of the
gastrointestinal tract of animals are highly similar. In mouse
and chicken embryos, gut formation is initiated by the formation
of two open-ended tubes at opposite sites of the embryo. The
tubes are generated by the invagination of the endodermal layer
in an anterior-ventral position and later in a posterior-ventral
region. The gut tubes then grow and extend toward each other
until they meet and fuse around the yolk stalk. In the fruit fly
Drosophila, gut formation is also initiated with gastrulation by
the invagination of cells of the anterior-ventral and posterior-
dorsal region of the embryo to give rise to the foregut and
hindgut primordial tubes, respectively. The midgut forms in
between these tubes by fusion of an anterior and a posterior
primordium. As the gut tubes form, visceral mesoderm is recruited
to surround the invaginating gut epithelia.

2) The primitive gut tube of vertebrates and invertebrates is
initially regionalized along the anterior-posterior axis into
three broad domains: the foregut, the midgut, and the hindgut.
Ultimately, these domains are further subdivided, and derived
organs such as the lungs, pancreas, or liver in vertebrates, and
the proventriculus or the Malpighian tubules in Drosophila, are
specified. The similarity of the morphological processes during
gut formation is paralleled by the function of evolutionarily
conserved molecular regulators of gastrointestinal development.

Current Biology 2002 12:171

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7. ON BODY PATTERNING IN DEVELOPMENT

Y. Takahashi et al (Nara Institute of Science and Technology, JP)
discuss body patterning, the authors making the following points:

1) Ontogenesis (the developmental processes of an individual
animal) begins with a fertilized egg, and through proliferation,
this single cell becomes a homogeneous mass of cells. This mass
of cells then becomes subdivided into distinct groups that
eventually will exhibit functional specialization later in
development. If the units fail to be correctly established in
time and space, certain specializations might be entirely missing
from the embryo, or cells might randomly differentiate
(specialize) in the wrong place. Furthermore, cells specializing
in the wrong place may end up dying because they fail to be
properly integrated with the rest of the organism. All of these
outcomes can have dire effects on the body.

2) The progress of organogenesis is governed by patterning
processes that have occurred earlier during development and that
involve the action of cell-cell signaling pathways, growth
factors acting between cells, and transcription factors acting
within cells. In general, both body segmentation and brain
patterning are essential for conferring a highly organized
functional complexity to the body. In both cases, an originally
homogeneous group of cells obtains characteristics to give rise
to particular structures and functions in a precise spatial and
temporal pattern. This produces patterns such as the regular
repetition of skeletal elements and the 3-dimensional
compartments of brain primordium on which the subsequent
complexity of the neuronal network is organized. It is now widely
accepted that similar sets of factors are shared by different
animal species and also by distinct processes in the course of
early patterning of organogenesis. During animal evolution, a
"prepattern" of fundamental organs apparently emerged relatively
early.

Proc. Nat. Acad. Sci. 2001 98:12338

Related Background Brief:

HOX GENES AND THE DIVERSIFICATION OF INSECT AND CRUSTACEAN BODY
PLANS. Crustaceans and insects share a common origin of
segmentation, but the specialization of trunk segments appears to
have arisen independently in insects and various crustacean
subgroups. Such macroevolutionary changes in body architecture
may be investigated by comparative studies of conserved genetic
markers. The Hox genes are well suited for this purpose, as they
determine positional identity along the body axis in a wide range
of animals. The authors examine the expression of four Hox genes
in the branchiopod crustacean Artemia franciscana, and compare
this with Hox expression patterns from insects. In Artemia the
three "trunk" genes Antp, Ubx and abdA are expressed in largely
overlapping domains in the uniform thoracic region, whereas in
insects they specify distinct segment types within the thorax and
abdomen. The authors suggest their comparisons indicate a
multistep process for the diversification of these Hox gene
functions, involving early differences in tissue specificity and
the later acquisition of a role in defining segmental differences
within the trunk. The authors propose that the branchiopod thorax
may be homologous to the entire pregenital (thoracic and
abdominal) region of the insect trunk. M. Averof and M. Akam:
Nature 1995 376:420.

Related Background Brief:

A CONSERVED SYSTEM FOR DORSAL-VENTRAL PATTERNING IN INSECTS AND
VERTEBRATES INVOLVING SOG AND CHORDIN. Dorsal-ventral patterning
within the ectoderm of the Drosophila embryo requires seven
zygotic genes, including short gastrulation (sog). The authors
demonstrate that sog, which is expressed in the ventrolateral
region of the embryo that gives rise to the nerve cord, is
functionally homologous to the chordin gene of Xenopus, which is
expressed in the dorsal blastopore lip of the embryo and in
dorsal mesoderm, in particular in the notochord. The authors
demonstrate show by injections of messenger RNA that both sog and
chordin can promote ventral development in Drosophila, and that
sog, like chordin, can promote dorsal development in Xenopus. In
Drosophila, sog antagonizes the dorsalizing effects of
decapentaplegic (dpp), a member of the transforming growth
factor-beta family. One of the dpp homologues in vertebrates,
bmp-4, is expressed ventrally in Xenopus and promotes ventral
development. The authors demonstrate that dpp can promote ventral
fates in Xenopus, and that injection of sog mRNA counteracts the
ventralizing effects of dpp. The authors suggest these results
indicate the molecular conservation of dorsoventral patterning
mechanisms during evolution. S.A. Holley et al: Nature 1995
376:210.

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8. ON THE DEVELOPMENT OF THE BRAIN

Melvin Konner (Emory University, US) discusses the development of
the brain, the author making the following points:

1) The author poses "Changeux's paradox": how do 30,000 human
genes determine 10^(11) cells with 10^(15) connections? Obviously
they can't do it in the same way that the roundworm's 18,000
genes govern its 959 cells. There are several solutions:

2) First, pioneer cells and axons pave the way for thousands or
tens of thousands of others to track their guidance, offering
lots of hook-ups for the price of one. Second, the mammalian
brain forms many more cells and connections than it needs,
subsequently pruning back around half of them. Some of this
occurs through programmed cell death, but much depends on
activity -- meaning that spontaneous and reactive fetal movements
shape the brain. Third, small groups of neurons may form under
strict genetic control -- creating small, deterministically wired
systems similar to the roundworm's brain -- and then compete for
incoming stimulation and outgoing actions.

3) These processes have been called "darwinian", but this is only
a partial analogy. The cells of the embryo are genetically
identical, and they produce no offspring, thus undermining two
pillars of Darwin's theory --variation and inheritance. Still,
the processes involve competition, which is resolved by
environmental, adaptive selection. And the cells are not quite
genetically identical -- the same set of genes is always there,
but only some are switched on. Which switch on and which off in
any given cell -- and when, and how, and why -- determine the
cell's character and function. A main key to development is this
on off pattern, a pulsing, embryo-wide light show that turns
genetic instructions into animals.

4) Elucidating the control of these switches -- by signals inside
the cell, beyond it, or even outside the body --is the main task
of biology in the 21st century. And the switches are not flipped
just in early life -- genes that confer Huntington's and
Alzheimer's diseases are switched on decades after the die is
cast. But of course, in a complex animal, much is left to chance.
Chaos in the formal sense -- exquisite sensitivity to variations
in starting conditions -- cumulatively amplifies small
differences. This embryonic butterfly effect gives identical
twins different brains within weeks of conception. Such
unpredictable paths help to explain why twins differ before we
even consider their environmental influences.

References (abridged):

1. Anastasi, A. Psychol. Rev. 65, 197 208 (1958).

2. Changeux, J.-P. Neuronal Man: The Biology of Mind (trans.
Garey, L.; Princeton Univ. Press, 1997).

3. Edelman, G. M. Neural Darwinism: The Theory of Neuronal Group
Selection (Basic, New York, 1987).

4. Wolpert, L. The Triumph of the Embryo (Oxford Univ. Press,
1991).

Nature 2002 418:279

Related Background:

ON THE BRAINS OF MICE AND HUMANS

"No category of cell, no particular type of circuit is specific
to the human cerebral cortex. The components of our cerebral
machinery derive from a stock very similar, if not identical, to
that of the mouse. The major event in the evolution of the
mammalian brain is the expansion of the neocortex. This growth is
accompanied by an increase in the total number of neurons, and
thus in the number and complexity of the operations which the
cortex can perform. The number of cellular elements per unit of
surface area has not changed. The cortical thickness varies, but
much less than its surface area. On average, the cortex of man is
only three times thicker than that of the mouse, although the
increase is not uniform in all layers... The more the surface
area of the cortex expands, the more the number of neurons
capable of establishing association connections increases... This
translates, finally, into an increase in the mean number of
connections per neuron, with a consequent burgeoning of the
dendritic and axonal trees, reaching a maximum in man.
Nevertheless, the increase in the mean number of synapses per
neuron is not directly proportional to the increase in cortical
area. Far from it. The density of synapses per cubic millimeter
of cortex is of the same order in the rat as in man... At the
levels of both the macroscopic anatomy of the cortex and its
microscopic architecture, no sudden qualitative reorganization
marks the passage from the "animal" brain to the human brain.
There is, on the contrary, a continuous _quantitative_ evolution
in the total number of neurons, the diversity of areas, the
number of possible connections between neurons, and, therefore,
the complexity of the neuronal networks that make up the cerebral
machine."

Jean-Pierre Changeux: Neuronal Man: The Biology of Mind; Oxford
University Press, Oxford 1985, p.66

Related Background:

MAPPING IN THE BRAIN

Pasko Rakic (Yale University, US) discusses mapping in the brain,
the author making the following points:

1) The brain can be thought of as a map in which the position of
its constituent neurons indicates what they do. Nowhere is this
more evident than in the cerebral cortex, which consists of
structurally distinct cellular (cytoarchitectonic) areas
responsible for functions as diverse as sensory perception, motor
control, and cognition.

2) Apparently, as the cerebral cortex evolved, the number of
cytoarchitectonic areas increased and the number of sensory
representations also increased. Interest in how the map of the
cerebral cortex develops in the embryo has been sustained by the
belief that the mechanisms of development can help explain the
emergence of human mental capacity during evolution.

3) Traditionally, it has been presumed that the embryonic
telencephalon first forms an equipotential sheet of cells that
then becomes specified by input from subcortical centers ("tabula
rasa model"). An alternative view -- derived from experimental
manipulations of cortical input to primate embryos --is that
cells of the embryonic cerebral vesicle themselves carry
intrinsic programs for species-specific cortical regionalization
("protomap model"). According to this hypothesis, some region-
specific cytoarchitectonic features can develop independently of
input. Indeed, the prefix "proto-" emphasizes the malleable
nature of this primordial map. Within this primordial map, it is
thought that cues generated within cortical neurons attract
appropriate input and cooperatively create a final area-specific
3-dimensional organization.

Science 2001 294:1011

Related Background:

ON NEURONAL MIGRATION IN DEVELOPMENT

Mary E. Hatten (Rockefeller University, US) discuss neuronal
migration during development, the author making the following
points:

1) The migration of immature neurons from germinal zones to
specific positions where axon-target interactions occur is a
critical step in the development of the synaptic circuitry of the
brain. During development of the worm Caenorhabditis elegans,
very few cells move from the positions where they are generated.
Only 12 cell populations migrate, including three classes of
neurons (HSN, CAN, and Q neuroblasts), somatic gonad precursors,
and sex myoblasts (1-3). The more complex body plan of the fruit
fly Drosophila is reflected in more widespread cell migration
(3). In vertebrates, many cells undergo remarkable cell
migrations, including the cells of the gonads, kidney, and the
immune and nervous systems. Neuronal migration culminates in the
formation of layered cortical structures in mammals where a novel
form of migration, across the radial plane of the neural tube,
develops.

2) Studies on neuronal migration in C. elegans have identified
numerous genes that encode chemoattractants or receptors
important for neuroblast migration along the body axis, either
along the dorsoventral (DV) axis or anterior-posterior (AP) axis.
The most studied of these is unc-6 (also called unc-6/Netrin1),
which is required for DV but not AP migrations in C. elegans.
unc-6 encodes a protein secreted by ventral midline cells, which
guides the migration of cells in the dorsal direction via the
receptor UNC5 and ventrally via the receptor UNC40 (4). UNC-
6/Netrin1 and its receptors are critical for early cell
migrations along the DV axis of vertebrates as well. With regard
to the AP axis of C. elegans, MIG13 is a transmembrane protein
that acts nonautonomously in anterior migrations of Q neurons (5)
The expression of MIG13 is regulated by Hox gene activity, such
that increasing doses of MIG13 causes cells to migrate further
anterior. In C. elegans, vab-8 functions in posterior migrations
(6). The vab-8 locus encodes two isoforms of an intracellular
protein, one of which contains a kinesin-like motor domain. The
general schema seen in C. elegans, of migrations along the
central axes of the embryo via global positioning system genes,
is now appreciated in vertebrate embryos.

3) In summary: Over the past decade, genetic analyses have
yielded a more molecular view of neuronal migration and its role
in central nervous system development. We now realize that many
of the molecular mechanisms that guide migrations in
invertebrates are recapitulated in the vertebrate nervous system.
These mechanisms guide dorsoventral and anterior-posterior
migrations and merge with radial migratory pathways that are
prominent in the development of the mammalian cortex. The author
discusses the choreography of these different migratory
mechanisms within the context of genetic approaches that have
defined their molecular mechanisms.

References (abridged):

1. R. Blelloch, C. Newman, J. Kimble, Curr. Opin. Cell Biol. 11,
608 (1999)

2. W. C. Forrester, E. Perens, J. A. Zallen, G. Garriga, Genetics
148, 151 (1998)

3. D. Montell, Development 126, 3035 (1999)

4. E. Hedgecock, J. Culotti, D. Hall, Neuron 4, 61 (1990)

5. M. Sym, N. Robinson, C. Kenyon, Cell 98, 25 (1999)

Science 2002 297:1660

Web Links: neuronal migration in development

Related Background Brief:

IDENTIFICATION OF CAENORHABDITIS ELEGANS GENES REQUIRED FOR
NEURONAL DIFFERENTIATION AND MIGRATION. To understand the
mechanisms that guide migrating cells, the authors report they
have been studying the embryonic migrations of the C. elegans
canal-associated neurons (CANs). The authors describe two screens
used to identify genes involved in CAN migration. First, the
authors screened for mutants that died as clear larvae (Clr) or
had withered tails (Wit), phenotypes displayed by animals lacking
normal CAN function. Second, the authors screened directly for
mutants with missing or misplaced CANs. The authors isolated and
characterized 30 mutants that defined 14 genes necessary for CAN
migration. The authors report that one of the genes, ceh-10,
specifies CAN fate. ceh-10 had been defined molecularly as
encoding a homeodomain protein expressed in the CANs. Mutations
that reduce ceh-10 function result in Wit animals with CANs that
are partially defective in their migrations. Mutations that
eliminate ceh-10 function result in Clr animals with CANs that
fail to migrate or express CEH-23, a CAN differentiation marker.
Null mutants also fail to express CEH-10, suggesting that CEH-10
regulates its own expression. Finally, the authors report that
ceh-10 is necessary for the differentiation of AIY and RMED, two
additional cells that express CEH-10. W.C. Forrestera et al:
Genetics 1998 148:151.

Related Background Brief:

THE GENETICS OF CELL MIGRATION IN DROSOPHILA MELANOGASTER AND
CAENORHABDITIS ELEGANS DEVELOPMENT. Cell migrations are found
throughout the animal kingdom and are among the most dramatic and
complex of cellular behaviors. Historically, the mechanics of
cell migration have been studied primarily in vitro, where cells
can be readily viewed and manipulated. However, genetic
approaches in relatively simple model organisms are yielding
additional insights into the molecular mechanisms underlying cell
movements and their regulation during development. The author
focuses on these simple model systems where we understand some of
the signaling and receptor molecules that stimulate and guide
cell movements. The chemotactic guidance factor encoded by the
Caenorhabditis elegans unc-6 locus, whose mammalian homolog is
Netrin, is perhaps the best known of the cell migration guidance
factors. In addition, receptor tyrosine kinases (RTKs), and FGF
receptors in particular, have emerged as key mediators of cell
migration in vivo, confirming the importance of molecules that
were initially identified and studied in cell culture. Somewhat
surprisingly, screens for mutations that affect primordial germ
cell migration in Drosophila have revealed that enzymes involved
in lipid metabolism play a role in guiding cell migration in
vivo, possibly by producing and/or degrading lipid
chemoattractants or chemorepellents. Cell adhesion molecules,
such as integrins, have been extensively characterized with
respect to their contribution to cell migration in vitro and
genetic evidence now supports a role for these receptors in
certain instances in vivo as well. The role for non-muscle myosin
in cell motility was controversial, but has now been demonstrated
genetically, at least in some cell types. Currently the best
characterized link between membrane receptor signaling and
regulation of the actin cytoskeleton is that provided by the Rho
family of small GTPases. Members of this family are clearly
essential for the migrations of some cells; however, key
questions remain concerning how chemoattractant and
chemorepellent signals are integrated within the cell and
transduced to the cytoskeleton to produce directed cell
migration. New types of genetic screens promise to fill in some
of these gaps in the near future. D.J. Montell: Development 1999
126:3035.

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