A Temporal Transcriptional Switch Governs Stem Cell Division, Neuronal Numbers, and Maintenance of Differentiation

Abstract

The importance of producing the correct numbers of neurons during development is illustrated by both evolutionary enhancement of cognitive capacities in larger brains, and developmental disorders of brain size. In humans, increased neuronal numbers during development is speculated to partly derive from a unique subtype of neural stem cells (NSCs) that undergo a phase of expansion through symmetric self-amplifying divisions before generating neurons. Symmetric amplification also appears to underlie adult neural stem maintenance in the mouse. However, the mechanisms regulating this behavior are unclear. We report the discovery of self-amplifying NSCs in Drosophila and show that they arise by a spatiotemporal conversion of classical self-renewing NSCs. This conversion is regulated by a temporal transition in the expression of proneural transcription factors prior to cell division. We find a causal link between stem cell self-amplification and increased neuronal numbers. We further show that the temporal transcriptional switch controls both stem cell division and subsequent neuronal differentiation. Mora et al. discover neural stem cells in the Drosophila brain that divide symmetrically to double their numbers before generating one of the largest neuronal lineages in the fly. Atonal, the transcription factor that regulates stem cell doubling, also programs the maintenance of a differentiated state in their daughter neurons.