Transcription factors Mash-1 and Prox-1 delineate early steps in differentiation of neural stem cells in the developing central nervous system

Like other tissues and organs in vertebrates, multipotential stem cells ser ve as the origin of diverse cell types during genesis of the mammalian cent ral nervous system (CNS), During early development, stem cells self-renew a nd increase their total cell numbers without overt differentiation. At late r stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step i n cell differentiation remain poorly understood. In this study, we present evidence that the expression and function of the neural-specific transcript ion factors Mash-1 and Prox-1 are involved in this process. In vivo, Mash-1 - and Prox-1-expressing cells were defined as a transient proliferating pop ulation that was molecularly distinct from self-renewing stem cells. By tak ing advantage of in vitro culture systems, we showed that induction of Mash -1 and Prox-1 coincided with an initial step of differentiation of stem cel ls. Furthermore, forced expression of Mash-1 led to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and upregulati on of Prox-1, suggesting that Mash-1 positively regulates cell differentiat ion. In support of these observations in vitro, we found specific defects i n cellular differentiation and loss of expression of Prox-1 in the developi ng brain of Mash-1 mutant mice in vivo. Thus, we propose that induction of Mash-1 and Prox-1 is one of the critical molecular events that control earl y development of the CNS.