LAUSR

The genesis of a mature complement of neurons is thought to require, at least in part, lineages in which neural progenitors have distinct identities recognized by exclusive expression of one or a few molecular markers. Nevertheless, limited progenitor types distinguished by specific markers and lineal progression through these subclasses cannot easily yield the magnitude of neuronal diversity in most regions of the nervous system. The late Verne Caviness, to whom this edition of Developmental Neuroscience is dedicated, recognized this mismatch. In his pioneering work on the histogenesis of the cerebral cortex, he acknowledged that additional flexibility was required to generate multiple classes of cortical projection and interneurons. This flexibility may be accomplished by establishing cell states in which levels rather than binary expression or repression of individual genes varies across each progenitor's shared transcriptome. Such states may reflect local, stochastic signaling via soluble factors or coincidence of cell surface ligand/receptor pairs in subsets of neighboring progenitors. This probabilistic, rather than determined, signaling could modify transcription levels via multiple pathways within an apparently uniform population of progenitors. Progenitor states, rather than lineal relationships between types may therefore underly neuronal diversity in most regions of the nervous system. Moreover, mechanisms that influence variation required for flexible progenitor states may be targets for pathological changes in a broad range of neurodevelopmental disorders, especially those with polygenic origins.