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Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001.

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Neuroscience. 2nd edition.

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The Molecular Basis of Neural Induction

The essential consequence of gastrulation and neurulation for the development of the nervous system is the emergence of a population of neural precursors from a subset of ectodermal cells. Through a variety of experimental manipulations, primarily involving transplantation of different portions of developing embryos, embryologists recognized early on that this process depends on signals arising from cells in the primitive pit and notochord. Because a wide variety of chemical agents and physical manipulations are able to mimic some of the effects of these endogenous signals, their nature remained a mystery for several decades. It is now clear that the generation of cell identity—of which neural induction is but one mechanism—results from the spatial and temporal control of different sets of genes by endogenous signaling molecules. These inducing signals—including those from the primitive pit and notochord—are, not surprisingly, molecules that modulate gene expression.

The increasingly sophisticated effort to understand exactly how these inductive signals work has therefore focused on molecules that can modify patterns of gene expression. An instructive example is retinoic acid, a derivative of vitamin A and a member of the steroid/thyroid superfamily of hormones (Box A). Retinoic acid activates a unique class of transcription factors—the retinoid receptors—that modulate the expression of a number of target genes. Peptide hormones provide another class of inductive signals, including those that belong to the fibroblast growth factor (FGF) and transforming growth factor (TGF) families. Another peptide hormone essential for neural induction is sonic hedgehog (shh). These molecules, like retinoic acid, are produced by a variety of embryonic tissues including the notochord, the floorplate, and the neural ectoderm itself; they bind to cell surface receptors, many of which are protein kinases. Some of these molecular signals have been implicated in determining the fates of specific classes of cells in the developing nervous system (Figure 22.3). For example, shh is essential for the differentiation of motor neurons in the ventral spinal cord, whereas a TGF family molecule called dorsalin is important for the establishment of dorsal cells in the spinal cord—including the neural crest. Signaling via these peptide hormones activates a cascade of subsequent gene expression in ectodermal cells. In general, if the signaling mediated by any of these molecules is disrupted, the early development of the nervous system is compromised.

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Box A

Retinoic Acid: Teratogen and Inductive Signal. In the early 1930s, investigators noticed that vitamin A deficiency during pregnancy in animals led to a variety of fetal malformations. The most severe abnormalities affected the developing brain, which (more...)

Figure 22.3. Location of some inductive signals in the developing neural tube.

Figure 22.3

Location of some inductive signals in the developing neural tube. Inductive signals are provided by either the notochord, the floorplate, the roofplate and dorsal ectoderm, or the somites. These signals act locally on either the ventral or dorsal neuroepithelium (more...)

A particularly intriguing aspect of molecular signals that influence neural induction is the mechanism by which one class of inductive signals—the bone morphogenetic proteins, or BMPs—cause neural differentiation. As the name suggests, these peptide hormones, which are members of the TGFfamily, elicit osteogenesis from mesodermal cells. If ectodermal cells are exposed to BMP, they assume an epidermal fate. How then does the ectoderm manage to become neuralized, especially since BMPs are produced by the notochord, floorplate, and somites? All of these structures are in position to signal to the neuroectoderm, and therefore to convert it to epidermis. This epidermal fate is evidently avoided in the neural plate by the local activity of other inductive signaling molecules called noggin and chordin. Both of these molecules bind directly to the BMPs and thus prevent their binding to BMP receptors. In this way, the neuroectoderm is “rescued” from becoming epidermis. Such negative regulation has led to the conclusion that becoming a neuron is actually the “default” fate for embryonic ectodermal cells.

This and other knowledge about the molecules involved in neural induction has provided a much more informed way of thinking about the etiology and prevention of a number of congenital disorders. Anomalies like spina bifida (failure of the posterior neural tube to close completely), anencephaly (failure of the anterior neural tube to close at all), and other brain malformations (often accompanied by mental retardation) probably result from defects in inductive signaling or the genes that participate in this process. As already descibed, excessive intake of vitamin A can impede neural tube closure and differentiation or disrupt later aspects of neuronal differentiation. Embryonic exposure to a variety of other drugs—alcohol and thalidomide are good examples—can also elicit pathological differentiation of the embryonic nervous system by providing inductive signals at inappropriate times or places. Furthermore, dietary insufficiency of substances like folic acid can disrupt neural tube formation by compromising cellular mechanisms essential for normal cell division and motility. Because the consequences of disordered neural induction are so severe, pregnant women are well advised to avoid virtually all drugs and dietary supplements—except those deemed safe and prescribed specifically by physicians—especially during the first trimester of pregnancy.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Sinauer Associates, Inc.
Bookshelf ID: NBK10823

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