Oligodendrocyte Specification in Zebrafish Requires Notch-Regulated Cyclin-Dependent Kinase Inhibitor Function

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Abstract
Cyclin-dependent kinase inhibitors (Cdkis) influence both cell-cycle progression and differentiation of neural cells. However, the precise roles of Cdkis in coordinating formation of neurons and glia and the mechanisms that regulate expression of genes that encode Cdkis in the vertebrate CNS remain unknown. Here, we report that, in zebrafish, expression of the Cdki gene cyclin-dependent kinase inhibitor 1c (cdkn1c), a p57 homolog, is negatively regulated by Delta-Notch signaling and that Cdkn1c function is required for neural plate cells to stop dividing and differentiate as neurons on schedule, even in the absence of Notch signaling activity. Furthermore, Cdkn1c function is required for specification of oligodendrocytes from ventral spinal cord precursors. We propose that levels of cdkn1c expression are an important factor in regulating neural development: high levels of Cdkn1c promote cell-cycle exit and neuronal development, whereas, during late embryogenesis, neural cells that have low but functional levels of Cdkn1c, regulated by Notch activity, are specified for oligodendrocyte fate.