Vertebrate Embryonic Cells Will Become Nerve Cells Unless Told Otherwise

Abstract

Although noggin, follistatin, and chordin can neuralize by antagonizing BMP4 epidermalizing activity, is it possible that, in addition, they transduce a signal via a receptor, as was originally postulated for noggin and chordin? The default model would predict not. There are indeed three lines of evidence that strongly argue against the existence of receptors for follistatin, noggin, or chordin, at least in the pathway mediating neuralization, and that inhibition of BMP signaling is sufficient to unveil the neural fate. First, there is the evidence from cell dissociation experiments discussed above: when embryonic cells are dissociated for several hours they will make neural tissue (3xNeural differentation of Xenopus laevis ectoderm takes place after disaggregation and delayed reaggregation without inducer. Grunz, H and Tacke, L. Cell Diff. Dev. 1989; 28: 211–218Crossref | PubMed | Scopus (157)See all References, 2xSingle cell analysis of mesoderm formation in the Xenopus embryo. Godsave, S.F and Slack, J.M.W. Development. 1991; 111: 523–530PubMedSee all References), and the addition of BMP4 will inhibit this effect and induce epidermis (Wilson and Hemmati-Brivanlou 1995xInduction of epidermis and inhibition of neural fate by Bmp-4. Wilson, P.A and Hemmati-Brivanlou, A. Nature. 1995; 376: 331–333Crossref | PubMedSee all ReferencesWilson and Hemmati-Brivanlou 1995). The second evidence comes from experiments recently performed in Drosophila. Holley et al. 1996xThe Xenopus dorsalizing factor noggin ventralizes Drosophila embryos by preventing DPP from activating its receptor. Holley, S, Neul, J, Attisano, L, Wrana, J, Sasai, Y, O'Connor, M, De Robertis, E, and Ferguson, E. Cell. 1996; 86: 607–617Abstract | Full Text | Full Text PDF | PubMed | Scopus (180)See all ReferencesHolley et al. 1996 demonstrate that at least for SOG/chd, and perhaps for noggin, binding DPP/BMP is their only function. They showed that while noggin inhibits DPP and phenocopies a dpp− mutation, it can only operate outside of the cell, and in the presence of an activated DPP receptor, its effect is abolished. More compelling is the fact that the double sog− dpp− mutant has the same phenotype as the dpp− mutant. If SOG had any other function than just inhibiting DPP, the double mutant phenotype should have been different than that of dpp− alone. The final line of evidence comes from the fact that, while chordin can reverse the osteogenic induction caused by BMP4 in 10T1/2 cell lines, it cannot block the one mediated by retinoic acid (Piccolo et al. 1996xDorsoventral patterning in Xenopus (inhibition of ventral signals by direct binding of chordin to BMP-4) . Piccolo, S, Sasai, Y, Lu, B, and De Robertis, E. Cell. 1996; 86: 589–598Abstract | Full Text | Full Text PDF | PubMed | Scopus (797)See all ReferencesPiccolo et al. 1996). Taken together, these observations strongly suggest that inhibition of BMP signaling is sufficient for neuralization.Contribution from many groups working with the amphibian system has provided a molecular solution to the problem of vertebrate neural induction originally defined by Spemann and Mangold. The challenge for the future will inevitably include the establishment of a link between the early neural specification process, described above, and the function of neurogenic genes operating downstream of these signaling events, ultimately leading to the generation of a mature neuron.