Vertebrate Embryonic Cells Review Will Become Nerve Cells Unless Told Otherwise

Ali Hemmati-Brivanlou* and Douglas Melton† (Spemann and Mangold, 1924). In the absence of this influence, as on the ventral side, the ectoderm differenti*Laboratory of Molecular Embryology The Rockefeller University ates as epidermis. Thus, in the following decades, the development of epidermis was assumed to be a fall1230 York Avenue New York, New York 10021–6399 back, or “default” fate for gastrula ectoderm, requiring no cell–cell communication, whereas neural specifica†Department of Molecular and Cellular Biology Howard Hughes Medical Institute tion was thought to be contingent upon the receipt of a positive signal (in molecular terms, a signal that actiHarvard University 7 Divinity Avenue vates a signal transduction pathway) from neighboring cells. Cambridge, Massachusetts 02138 A considerable effort over several decades failed to identify the gene products responsible for neural induction in the embryo. The idea of a positive signal involved The past few years have witnessed a significant change in neural induction so dominated thinking in the field in the understanding of how the vertebrate nervous systhat the significance of results inconsistent with this tem forms during embryogenesis. More than seventy idea were not widely appreciated. For example, several years since Spemann and Mangold first demonstrated researchers found that when cells of ectodermal exthe phenomenon of neural induction, the molecular plants (also called “animal caps”), were dissociated, mechanisms underlying neural induction now appear to they can form neural tissue whereas intact or whole be at hand. Two independent approaches, one focusing animal caps form epidermis (Grunz and Tacke, 1989; on a “default” or “ground-state” model for neural inducGodsave and Slack, 1991). In these experiments dorsal tion and the other culminating in the discovery of semesodermal tissue (the organizer) is absent and neuralicreted neural inducing factors (noggin, follistatin, and zation occurs in a cell autonomous fashion, in contradicchordin), have not only brought to a successful conclution with the requirement for a positive signal derived sion the search for Spemann’s neuralizing factor, but from the organizer. With hindsight these results using also illuminated its mechanism of action. It now appears simple cell dissociation provided a strong hint that neuthat neuralization of embryonic cells occurs when cells ral inhibitory signal(s) within the ectoderm, or the whole do not receive other inducing signals telling them to embryo, prevent neuralization, and in the case of animal form epidermis, mesoderm, or endoderm. This concept caps, these neural inhibitors or antagonists drive cells of neuralization allows for a reinterpretation of the classitoward an epidermal fate. cal views on both neural and epidermal specification. The secreted growth factor BMP4 (Bone Morphogenetic Neural, Not Epidermal, as the Default State Protein) plays a pivotal role wherein BMP signaling inof Embryonic Ectoderm duces epidermaldifferentiation. It is the absence of BMP It is important to distinguish between direct and indirect signaling, accomplished by BMP antagonists including effects in understanding assays for neural induction. noggin, follistatin, and chordin, that leads to the formation of neural tissue.