A low CDKN1c/p57 ^kip2 expression in spinal progenitors drives the transition from proliferative to neurogenic modes of division

During vertebrate neurogenesis, a progressive transition from symmetric proliferative to asymmetric neurogenic progenitor divisions is critical to balance growth and differentiation. We used single-cell RNA-seq data from chick embryonic neural tube to characterize the molecular mechanisms that drive this transition. Here we show that Cdkn1c, a key cell cycle regulator which is classically associated with neuronal cell cycle exit, plays an earlier role during neurogenesis by favoring a shift towards neurogenic mode of division. Cdkn1c expression progressively increases in neural progenitors, and its knock down leads to a reduction of neuron production, following a shortening of cell cycle mainly attributed to a reduction in G1 duration. Clonal analysis of pairs of sister cells indicates that reducing Cdkn1c expression in progenitors delays neurogenesis by favoring a symmetric proliferative mode of division. Combined CyclinD1 and Cdkn1c knockdowns restores the cell cycle defects and a wild-type distribution of modes of division, indicating that Cdkn1c acts via the regulation of cell cycle parameters. We propose a sequential role for Cdkn1c in neuron production, with its progressive expression in progenitors first promoting neurogenic division patterns via cell-cycle lengthening, before mediating cell cycle exit in daughter cells.