A low-level Cdkn1c/p57^kip2 expression in spinal progenitors drives the transition from proliferative to neurogenic...

During vertebrate neurogenesis, a transition from symmetric proliferative to asymmetric neurogenic divisions is critical to balance growth and differentiation. Using single-cell RNA-seq data from the chick embryonic neural tube, we identify the cell cycle regulator Cdkn1c as a key regulator of this transition. While Cdkn1 is classically associated with neuronal cell cycle exit, we show that its expression initiates at low levels in neurogenic progenitors. Functionally targeting the onset of this expression impacts the course of neurogenesis: Cdkn1c knockdown impairs neuron production by favoring proliferative symmetric divisions. Conversely, inducing a low-level Cdkn1c misexpression in self-expanding progenitors forces them to prematurely undergo neurogenic divisions. Cdkn1c exerts this effect primarily by inhibiting the CyclinD1-CDK4/6 complex and G1 phase lengthening. We propose that Cdkn1c acts as a dual driver of the neurogenic transition whose low level of expression first controls the progressive entry of progenitors into neurogenic modes of division before higher expression mediates cell cycle exit in daughter cells. This highlights that the precise control of neurogenesis regulators' expression sequentially imparts distinct functions essential for proper neural development.