All animals, including humans, begin life as a single cell. During the first few hours of development, that first cell and its progeny make a series of crucial decisions that ultimately lead to the formation of the organs and structures of the adult. One of the most important decisions the early embryo must make is how and where to form its nervous system, appropriately positioning the brain and the spinal cord as well as establishing the proper connections. The precursor of the nervous system in all vertebrates is a sheet of cells—the ectodermal layer. At the appropriate time, the ectodermal cells must decide between two possible fates: a neural identity on the dorsal side of the embryo or an epidermal one on the ventral side. Classical experiments using the amphibian embryo established that the nervous system forms in response to signals from the 'organizer', a group of dorsal, mesodermal cells underlying the ectoderm1. More recently, dissection of the molecular pathway underlying this inductive event revealed that this important cell fate decision is actually under the control of permissive signals rather than instructive ones (in molecular terms an instructive signal can be defined as a signal that is receptor-mediated and involves the activation of a signal transduction cascade, while permissive signals usually do not). This dissection led to the default model of neural induction in vertebrates, which posits that neural fate determination requires the abrogation of an inhibitory signal. These inhibitory signals have been identified as ligands of the TGFβ superfamily (more specifically, the branches comprised by the bone morphogenic proteins (BMPs) and growth and differentiation factors (GDFs)). The past few years have borne out the predictions of the default model: among other observations, it has now been demonstrated that interference with BMP signalling, at any level of the signalling cascade, leads to the same outcome: conversion of ectodermal cells from an epidermal to a neural fate2.
Shortly after the proposal of the default model, a transcription factor called NRSF (ref. 3), encoded by REST (ref. 4), was isolated and shown to be a repressor of a subset of neuronal specific genes in non-neural cells3,4,5,6. This, in addition to the finding that NRSF is mostly expressed in non-neural cells, suggested two important functions for NRSF: inhibition of neural-specific genes in differentiated non-neural cells and regulation of neural cell fate determination3,4. In fact, it was suggested that NRSF might be an endogenous repressor of neural cell fate (also known as the 'master regulator'3) which, in agreement with the default hypothesis, would itself need to be repressed in order for neural fate to be unveiled. Additional reports following shortly thereafter demonstrated that there are some exceptions to the rule: NSRF-binding sites were discovered in several non-neural genes6,7 and expression of the gene was detected in mature adult neurons8—findings that suggested a broader role for NSRF than originally expected.
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