Hox Genes Acting as Homeotic Genes (pp. 621)
Same Genes Controlling Dorsoventral Polarity in Flies and Frogs (pp. 627-629)
The progreess zone model of proximodistal pattern formation in the vertebrate limb has been called into question by new results of Dudley et al. (2002), reviewed by Saunders (2002). Within the progress zone (PZ) subjacent to the apical ectodermal ridge (AER), cells have been thought to undergo progressive distalization with the passage of time, perhaps as measure by the number of cell divisions. New data from fate mapping and transplantation experiments with chicken wing buds are not readily explained by the PZ model. Instead, they suggest that all proximodistal elements are specified early by signals from the AER, and that subsequent development involves just an expansion of different progenitor populations prior to differentiation. Thus, a better name for the limb bud zone capped by the AER may be "apical zone". Its extent may be defined by the rapid cell death that occurs after removal of the AER.
Dudley A.T., Ros M.A. and Tabin C.J. (2002) A re-examination of proximodistal patterning during vertebrate limb development. Nature 418: 539-544
Saunders J.W. (2002) Is the progress zone model a victim of progress? Cell 110: 541-543
Carroll S.B. (2000) Endless forms: The evolution of gene regulation and morphological diversity. Cell 101: 577-580
Ruvinsky I. and Gibson-Brown J.J. (2000) Genetic and developmental bases of serial homology in vertebrate limb evolution. Development 127: 5233-5244
Chang C., Holtzman D.A., Chau S., Chickering T., Woolf E.A., Holmgren L.M., Bodorova J., Gearing D.P., Holmes W.E. and Brivanlou A.H. (2001) Twisted gastrulation can function as a BMP antagonist. Nature 410: 483-487
Oelgeschlager M., Larrain J., Geissert D. and De Robertis E.M. (2000) The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405: 757-763
Ross J.J., Shimmi O., Vilmos P., Petryk A., Kim H., Gaudenz K., Hermanson S., Ekker S.C., O'Connor M.B. and Marsh J.L. (2001) Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410: 479-483
Scott I.C., Blitz I.L., Pappano W.N., Maas
S.A., Cho K.W. and Greenspan D.S. (2001) Homologues of Twisted
gastrulation are extracellular cofactors in antagonism of BMP
signalling. Nature 410: 475-478.
These four studies investigate the Drosophila protein Twisted gastrulation (Tsg), and its homologs in zebrafish, frog, and chicken, as a new cofactor in BMP signaling. In Drosophila embryos, the BMP-type molecule Decapentaplegic (Dpp) specifies at least three elements of the dorsoventral body pattern: amnioserosa (highest Dpp), epidermis (intermediate Dpp), and neurogenic ectoderm (no Dpp). The Dpp gradient is shaped in part by Short gastrulation (Sog), which binds to and inhibits Dpp. In turn, Sog is antagonized by Tolloid, a protease that brakes down Sog and releases Dpp. The role of the new player, Tsg, seems to be two-fold. By binding to Dpp/Sog, Tsg prevents the binding of Dpp to its receptor and accelerates the diffusion of Dpp. By accelerating the breakdown of bound Sog by Tolloid, Tsg also enhances the recovery of active Dpp. The overall effect depends on the concentration of Sog. Where Sog is abundant (ventrolaterally), the effect of Tld is overpowered, and Dpp remains bound up. Where Sog is scarce (dorsally), Tld degrades Sog and releases active Dpp. This explains why the highest Dpp activity is reached at some distance from maximal Sog concentration, an effect that may also involve an inhibition of the Tld+ gene by the Brinker transcriptional inhibitor (see update 22D). The vertebrate homologs of Tsg promote the binding of chordin (Sog homolog) to BMP4, enhance the cleavage of chordin by Tld homologs, and potentiate chordin's ability to induce secondary axes in Xenopus. These observations confirm and extend the previous observations on the evolutionary conservation of BMP type signaling in the specification of the dorsoventral body pattern.
Dahn R.D. and Fallon J.F. (2000) Interdigital
regulation of digit identity and homeotic transformation by
modulated BMP signaling. Science 289: 438-441
The investigators used advanced microsurgical techniques to manipulate chicken limb buds and found that the identity of the digits is determined at advanced stages of development and by interdigital tissue. By splitting and transplanting digit precursors, they found that digit identity is specified by the interdigital mesoderm before the latter regresses through apoptosis. Each primordium develops according to the most posterior clues it receives. Digit identity was transformed if bone morphogenetic protein signaling was boosted or inhibited, suggesting a role for BMPs in the specification process.
Litingtung Y, Dahn RD, Li Y, Fallon JF, Chiang
C. (2002) Shh and Gli3 are dispensable for limb skeleton
formation but regulate digit number and identity. Nature
Sonic hedgehog (Shh) protein is thought to specify digit identity through dose-dependent activation of homeotic target gene expression. However, the regulatory mechanisms involved remain poorly understood. This study focuses on Gli3, a transcriptional regulator that can act as an activator or repressor dependent on Shh. The investigators report genetic analyses in mice showing that Shh and Gli3 are dispensable for formation of limb skeletal elements: Gli3(-/-) as well as Shh(-/-) Gli3(-/-) limbs are distally complete and polydactylous, but completely lack wild-type digit identities. They propose that the function of Shh and Gli3 in limb skeletal patterning is limited to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification, by regulating the relative balance of Gli3 transcriptional activator and repressor activities.
Yekta S., Shih I. and Bartel D.P. (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594-596
The investigators fpound that miR-196, a miRNA encoded at three paralogous locations in the A, B, and C mammalian HOX clusters, has extensive, evolutionarily conserved complementarity to messages of HOXB8, HOXC8, and HOXD8. RNA fragments indicating miR-196-directed cleavage of HOXB8 were detected in mouse embryos. Cell culture experiments demonstrated down-regulation of HOXB8, HOXC8, HOXD8, and HOXA7 and supported the cleavage mechanism for miR-196-directed repression of HOXB8. These results point to a miRNA-mediated mechanism for the posttranscriptional restriction of HOX gene expression during vertebrate development and demonstrate that metazoan miRNAs can repress expression of their natural targets through mRNA cleavage in addition to inhibiting translation.
Wellik D.M. and Capecchi M.R. (2003) Hox10 and Hox11 genes are required to globally pattern the
mammalian skeleton. Science 301: 363-367
The researchers constructed mice homozygous for loss-of-function alleles in all Hox10 or all Hox11genes. Since cluster B does not have Hox10 or Hox11 genes, there are 2x3=6 gene in each of these pseudo-orthologous groups. All of them needed to be mutated to produce a phenotype. In the absence of Hox10 function, no lumbar vertebrae were formed. Instead, ribs projected from all posterior vertebrae, extending from the thorax to beyond the sacral region. In the absence of Hox11 function, sacral vertebrae were not formed, and instead these vertebrae assumed a lumbar identity.
Great SEMs and drawings of mouse and human embryonic development may be found on this web site, which is slated for additional illustrations of pre-implantation and fetal development as well as the genesis of birth defects.
The Multidimensional Human Embryo is funded by the National Institute of Child Health and Human Development (NICHD) and provides a three-dimensional image reference of the Human Embryo based on magnetic resonance imaging.
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