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ScienceWeek
DEVELOPMENT: GENE EXPRESSION AND CELL TYPES IN THE BRAIN
The following points are made by R.V. Pearse II and C.J Tabin (Nature 2006 439:404):
1) While forming functional domains in the developing brain, cells crawl considerable distances to reach their final destinations. So it has been extremely difficult to determine when and where during this process the neuronal cells "learn" which distinct brain region they are fated to become. But advances in mouse genetic manipulation now allow researchers to indelibly mark a cell population at a discrete place and time in development, based on its gene-expression pattern, and to follow the cells' subsequent progress[1,2]. A series of papers[3,4,5] have exploited these innovations to trace the "decisions" of cells to form certain brain centers (nuclei) back to instructions in the developing neural tube in the embryo.
2) The embryonic neural tube gives rise to the brain and spinal cord, and is one of the best-studied models of how spatial organization of a structure emerges during development. In the neural tube that will give rise to the spinal cord, fate specification takes place essentially along a two-dimensional cartesian grid. Distinct sets of transcription factors are expressed at various locations within this grid, establishing unique progenitor populations.
3) These factors regulate groups of target genes, setting in motion a developmental program that defines the ultimate fate of cells derived from each progenitor population. The progenitor domains can be repeatedly divided into ever smaller sub-domains, each defined by one or more transcription factor(s). The cells derived from these pools can either stay put or move short distances radially, while basically maintaining their dorsal ventral relationships.
4) In the developing brain, the situation is much more complex. In many regions there are so-called germinal zones, which serve as a source of progenitor cells. These cells migrate along complicated pathways, both laterally and radially, ending up next to neighbors that are quite distinct from the cells that were near them in the germinal zone. Moreover, single progenitor cells within a germinal zone can give rise to daughter cells that end up in different regions and adopt dissimilar fates.
References (abridged):
1. Zinyk, D. L. , Mercer, E. H. , Harris, E. , Anderson, D. J. & Joyner, A. L. Curr. Biol. 8, 665 668 (1998)
2. Branda, C. S. & Dymecki, S. M. Dev. Cell 6, 7 28 (2004)
3. Machold, R. & Fishell, G. Neuron 48, 17 24 (2005)
4. Wang, V. Y. et al. Neuron 48, 31 43 (2005)
5. Landsberg, R. I. et al. Neuron 48, 933 947 (2005)
Nature http://www.nature.com/nature
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MORPHOGENESIS: THE NEURAL TUBE AND THE PROTEIN SHROOM
The following points are made by Paul Martin (Current Biology 2004 14:R150):
1) Animal embryos are shaped during development by a series of morphogenetic episodes which frequently involve the tugging, bending, folding and sculpting of epithelial sheets. One such morphogenetic process in vertebrates, neural tube closure, is well studied and of clinical importance because when it goes wrong the consequences are dire -- failure of cranial neural tube closure results in anencephaly and death at birth, while if the caudal neural tube fails to fully zipper closed, then the infant will be born with spina bifida.
2) Several years ago, "Shroom", a novel molecular regulator of this process was identified in a gene trap mutagenesis screen. Homozygous shroom mutant mice generally exhibited anencephaly, which made their developing brain bulge out like a wild mushroom; much less frequently they also had spina bifida [1]. When the gene was cloned, Shroom turned out to be a novel actin-binding protein. A recent study[2] shows how ectopic Shroom can direct naive strips of Xenopus ectoderm, or even sheets of confluent epithelial cell lines, to constrict and fold. Shroom localizes to the apical edges of cells destined to constrict in the Xenopus neural plate and appears to mediate this constriction via the small GTPase switches, Rap and Ras.
3) Most, if not all, of the epithelial foldings and bendings that underlie morphogenesis of a vertebrate embryo involve concerted contraction of the apical surfaces of groups of cells. These cells convert their shape from cuboidal to wedge-like, and this forces the epithelium to contort. In this way, for example, patches of ectoderm will invaginate on either side of the embryonic head to convert otic placodes sequentially into otic cups and then otic pits, which finally bud off as otic vesicles to form the left and right inner ears [3]. Similarly, cells of the neural plate constrict to varying degrees to drive the neural lips upwards and toward one another until they meet and fuse in the midline to form the neural tube, which will eventually become the organism's brain and spinal cord.
4) Besides apical constriction of cells within the neural epithelium, at least two other forces appear to collaborate to fold the neural plate -- one of these forces derives from the pushing pressure of adjacent dorsolateral ectoderm, and another is due to proliferative pressures within the neurepithelium [4]. In the trunk and tail end of the embryo, these other forces seem dominant and tube closure is not disrupted by exposure of cultured mouse embryos to cytochalasins, but cranial neural tube closure is exquisitely sensitive to these actin microfilament dissolving drugs which generally cause anencephaly [5], just as seen in shroom mutant embryos.
References (abridged):
1 Hildebrand, J.D. and Soriano, P. (1999). Shroom, a PDZ domain-containing actin-binding protein, is required for neural tube morphogenesis in mice. Cell 99, 485-497
2 Haigo, S.L., Hildebrand, J.D., Harland, R.M., and Wallingford, J.B. (2004). Shroom induces apical constriction and is required for hingepoint formation during neural tube closure. Curr. Biol. 13, 2125-2137
3 McPhee, J.R. and Van de Water, T.R. (1986). Epithelial-mesenchymal tissue interactions guiding otic capsule formation: the role of the otocyst. J. Embryol. Exp. Morphol. 97, 1-24
4 Colas, J.F. and Schoenwolf, G.C. (2001). Towards a cellular and molecular understanding of neurulation. Dev. Dyn. 221, 117-145
5 Morriss-Kay, G. and Tuckett, F. (1985). The role of microfilaments in cranial neurulation in rat embryos: effects of short-term exposure to cytochalasin D. J. Embryol. Exp. Morphol. 88, 333-348
Current Biology http://www.current-biology.com
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EMBRYOGENESIS AND GENE EXPRESSION
The following points are made by T. Kudoh et al (Genome Research 2001 11:1979):
1) Embryonic development is accompanied by regulated changes in the expression of large sets of genes, and determining how the interplay of these changes influences the progress of development at the cellular and organismic level is a major aim of developmental biology. In the past several decades it has become clear that the expression and function of a variety of regulatory genes guide developmental processes such as cell differentiation and pattern formation, and it has also emerged that a highly effective way of approaching questions of developmental mechanism is to study the properties of differentially regulated gene expression during embryogenesis.
2) This approach has been applied to vertebrate systems in a variety of ways. Earlier studies emphasized specific aspects of developmental control by selecting genes for study according to various criteria, including temporal patterns of expression, regional restriction, and functional characteristics. Such approaches have led to a wealth of information about gene expression patterns, providing useful regional markers, and yielding insights into regulatory factors that control differentiation and pattern formation.
3) As developmental biology entered the genomic era, a notion that gained currency was that it may not only be desirable but also feasible to characterize the regulated expression of the entire population of genes that affect embryogenesis, rather than focus on selected subsets of genes. But even in cases where a complete genome sequence is available, this aim is quite large. Instead, by placing the focus on those genes whose expression is spatially and temporally regulated during development, the total numbers of genes that need to be studied is reduced and the yield of useful information is increased. Screens of this type have now been carried out with Xenopus (African clawed toad), mouse embryos, and zebrafish (Danio rerio).
Genome Research http://www.genome.org
ScienceWeek http://scienceweek.com
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