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ScienceWeek
DEVELOPMENTAL BIOLOGY: ON MORPHOGENS
The following points are made by G. Yucel and S. Small (Current Biology 2006 16:R29):
1) The idea that gradients of morphogens are involved in patterning complex embryo body plans has a long history in developmental biology. The morphogen idea was first postulated by Morgan at the beginning of the 20th century, but it was Wolpert [1] who refined the idea in the 1960s. He proposed that different genes would be turned on in response to different threshold concentrations of the morphogen. In Wolpert's French flag model, these states were represented by different colors, with high concentrations turning on a blue gene, lower concentrations turning on a white gene, with red a default state in regions of the embryo below the threshold.
2) The first morphogen known molecularly was Bicoid (Bcd), a homeodomain-containing transcription factor that is critical for the establishment and placement of all anterior structures in the Drosophila body plan. The experimental evidence supporting Bcd as a morphogen is very convincing. Embryos containing different copy numbers of the bcd gene show dramatic shifts of landmark structures along the anterior posterior (AP) axis [2]. For example, the cephalic furrow, one of the first distinguishable morphological features, is shifted posteriorly in embryos that contain four or six copies of the bcd gene.
3) bcd mRNA is anchored by the cytoskeleton to the anterior tip of the oocyte [3]. When eggs are laid, bcd mRNA is translated, and a gradient of protein is formed, with highest levels near the anterior tip of the embryo, and progressively lower levels toward posterior regions [4]. The shape of the gradient is thought to be controlled by a combination of the rates of translation, diffusion, and degradation.
4) While the Bcd protein gradient is forming, zygotic nuclei are undergoing ten very rapid division cycles and migrate to the periphery of the embryo and the early cytoplasmic gradient is converted into a nuclear gradient. The total amount of Bcd protein in the embryo increases until the beginning of division cycle 14, from when its expression starts to decline [4]. The peripheral migration of the nuclei coincides with the onset of zygotic transcription, and the zygotic genes hunchback (hb) and orthodenticle (otd) are among the first to be turned on by Bcd. hb is expressed throughout the anterior half of the embryo, while otd is expressed in only the anterior-most 30% [5]. Initially, these expression patterns are diffuse, but they are refined during nuclear division cycle 14, exhibiting sharp posterior boundaries that are precisely positioned along the AP axis and show very little variation between individual embryos.
References (abridged):
1. L. Wolpert, Positional information and the spatial pattern of cellular differentiation, J. Theor. Biol. 25 (1969), pp. 1 47
2. W. Driever and C. Nusslein-Volhard, The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner, Cell 54 (1988), pp. 95 104
3. T. Berleth, M. Burri, G. Thoma, D. Bopp, S. Richstein, G. Frigerio, M. Noll and C. Nusslein-Volhard, The role of localization of bicoid RNA in organizing the anterior pattern of the Drosophila embryo, EMBO J. 7 (1988), pp. 1749 1756
4. W. Driever and C. Nusslein-Volhard, A gradient of bicoid protein in Drosophila embryos, Cell 54 (1988), pp. 83 93
5. Q. Gao and R. Finkelstein, Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen, Development 125 (1998), pp. 4185 4193
Current Biology http://www.current-biology.com
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EVOLUTIONARY BIOLOGY: ON THE EVOLUTION OF DEVELOPMENT
The following points are made by A. Richard Palmer (Science 2004 306:828):
1) Mushrooming information on molecular mechanisms of development, coupled with increasingly robust phylogenetic trees, offers potentially revolutionary insights into how development evolves (1-3). But general hypotheses remain hard to test because organisms differ so much in form. Evolutionary novelties pose an acute problem because comparable traits, such as wings or image-forming eyes, have emerged too few times independently to allow multiple tests. Informative insights should come most readily from traits that (i) are well defined and unburdened by troublesome semantics, (ii) are easy to compare anatomically and developmentally, and (iii) have evolved multiple times independently. Bilateral asymmetries meet these criteria nicely.
2) Left-right asymmetry offers a particularly attractive focus for comparative studies because of its binary-switch nature. This simplicity follows naturally from the arrangement of developmental axes. The coordinate system that provides positional information to developing organisms has a property that is often unappreciated: It consists of four axes, not three. Although the anteroposterior and dorsoventral axes, which define the midplane, are both single axes, no single "left-right axis" exists because no single gradient extends from left to right. Rather, "left" and "right" axes are separate mediolateral axes that originate at and extend in opposite directions away from the midplane (4). Because these two mediolateral axes are mirror images, an extra symmetry-breaking step must occur for one to differ from the other (5). This implies bilateral symmetry is a default state once the anteroposterior and dorsoventral axes are defined, just as radial symmetry is the default state when only one axis exists. So, for example, in a bilaterally symmetrical organism, only one program is needed to specify a limb (2), but it yields paired, symmetrical limbs because additional information is required to prevent such symmetry.
3) Left-right differences, therefore, arise because some kind of switch causes the mediolateral axis on one side to differ from the axis on the other side (4), although the mechanisms remain unclear for most organisms. Both the origin of this simple binary switch and the subsequent evolution of developmental systems underlying it may be readily compared among taxa of widely differing form. Furthermore, conspicuous asymmetries have evolved independently in many animals and plants, so far-reaching generalizations are possible.
4) In summary: Because of its simplicity, the binary-switch nature of left-right asymmetry permits meaningful comparisons among many different organisms. Phylogenetic analyses of asymmetry variation, inheritance, and molecular mechanisms reveal unexpected insights into how development evolves. First, directional asymmetry, an evolutionary novelty, arose from nonheritable origins almost as often as from mutations, implying that genetic assimilation ("phenotype precedes genotype") is a common mode of evolution. Second, the molecular pathway directing the heart leftward -- the nodal cascade -- varies considerably among vertebrates (homology of form does not require homology of development) and was possibly co-opted from a preexisting asymmetrical chordate organ system. Finally, declining frequencies of spontaneous asymmetry reversal throughout vertebrate evolution suggest that heart development has become more canalized.
References (abridged):
1. W. Arthur, Nature 415, 757 (2002)
2. N. Shubin, C. J. Tabin, S. B. Carroll, Nature 388, 639 (1997)
3. A. S. Wilkins, The Evolution of Developmental Pathways (Sinauer, Sunderland, MA, 2002)
4. H. Meinhardt, Int. J. Dev. Biol. 45, 177 (2001)
5. N. A. Brown, L. Wolpert, Development 109, 1 (1990)
Science http://www.sciencemag.org
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CELL BIOLOGY: ON LEFT-RIGHT ASYMMETRY IN SNAILS
The following points are made by J. Wandelt and L.M. Nagy (Current Biology 2004 14:R654):
1) Metazoans, by and large, possess a simple bilateral symmetry. This symmetry is, however, rarely perfect. Most animals exhibit a distinct left-right asymmetry of some internal organs, while appearing bilaterally symmetric on the outside. For example, vertebrates show asymmetries in the position and morphology of the heart, liver, and gut, whereas in nematodes, structures such as the gonad and intestine are asymmetric [1,2]. Snails (Gastropoda), however, are unusual in their asymmetric external appearance, which is apparent in the way the shell coils. If the shell is viewed from the side and its tip is held upright, the opening of the shell can be either to the left-hand side (sinistral) or to the right-hand side (dextral) of the midline.
2) Most gastropod species show a uniform handedness, and reversal of this asymmetry is rare in nature. Most snail species are dextral, except, for example, the common pond snail Physa, which is an entirely sinistral species. Another common pond snail, Lymnaea is notable in that both dextral and sinistral forms are found in nature, with sinistral individuals representing up to 2% of the population. Consequently, Lymnaea and Physa have long been handy models for studying the genetics and development of left-right asymmetry.
3) Left-right asymmetry can be traced back as far as the first division in the spiral cleavage pattern of snail embryos [4,5]. Spiral cleavage is characterized by the oblique angle of the early cleavage planes and the alternation of direction of successive divisions. Thus, if odd numbered divisions are oriented clockwise (dextrotropic), the even divisions are counter-clockwise (levotropic). For reasons that remain unknown, the cleavage geometry correlates almost perfectly with adult handedness.
4) H.E. Crampton (1894) was among the first to describe how cleavages in sinistral Physa and dextral Lymnaea embryos were the mirror-image pattern of one another. He attributed the reversed orientation of division to a reversal of spindle inclination and cleavage plane, as did Freeman and Lundelius (1982) in their observations of dextral and sinistral embryos that occur within a single species of Lymnaea. In this view, spiral cleavage is controlled by an asymmetry in the cortex that regulates the inclination of the mitotic apparatus prior to cytokinesis. By contrast, Meshcheryakov and Beloussov (5) attributed the reversal of cleavage pattern between sinistral and dextral species to a reversal -- from clockwise to anti-clockwise -- of the spiral rotation of the daughter micromeres during cytokinesis. These rotations were independent of the orientation of the spindle. According to both models, the reversal of handedness is caused by a reversal of cellular machinery. The discrepancies between these two views have yet to be resolved.
5) Shibazaki et al (3) approach the question of handedness through a detailed analysis of the cytoskeletal dynamics during early cleavage in Physa and Lymnaea. They observe that in dextrally cleaving Lymnaea embryos, the mitotic spindles are oriented in a clockwise direction (when viewed from the animal pole) during metaphase-anaphase. At this stage, they also observe that the cells protrude, or deform, along the same axis as the spindle. The sinistral embryos of Physa show similar changes of spindle orientation and overall cell shape, but in the reverse direction.
6) The work of Shibazaki et al (3) demonstrates that there is presumably more than one way to generate and revert the spiral cleavage pattern. While spindle inclination and micromere rotation have been described previously [4,5], this is the first report to implicate the two mechanisms in the reversal of handedness within one species.
References (abridged):
1. Mercola, M. (2003). Left-right asymmetry: Nodal points. J. Cell Sci. 116, 3251-3257
2. Wood, W.B. (1998). Handed asymmetry in nematodes. Cell Dev. Biol. 9, 53-60
3. Shibazaki, Y.X Shimizu, M. and Kuroda, R. (2004). Body handedness is directed by genetically-determined cytoskeletal dynamics in the early embryo. Curr. Biol. 14:1462
4. Conklin, E.G. (1902). Karyokinesis and cytokinesis in the maturation, fertilization and cleavage of Crepidula and other Gasteropoda. J. Acad. Nat. Sci. Phil. 12, 1-121
5. Meshcheryakov, V.N. and Beloussov, L.V. (1975). Asymmetrical rotations of blastomeres in early cleavage of gastropoda. Wilhem Roux's Arch. 177, 193-203
Current Biology http://www.current-biology.com
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