Cyclin-dependent kinase inhibitors sequentially determine the neural-glial lineage boundaries in the developing cortex

초록

Neural stem cells (NSCs) can generate neurons and glia, but the regulatory mechanisms that invoke different lineages are largely unclear. Here, we addressed the role of cyclin-dependent kinase inhibitors (CDKIs) in the later stage of dorsal cortical development. We found upregulation of p18 and p27 among CDKIs at the onset of astrocyte generation. Acute manipulations of p18 and p27 levels showed that CDKIs modulated lineage switching between upper-layer neurons and astrocytes at the transitional stage. We then generated a conditional knock-in mouse to induce p18 in NSCs. The transcriptomic deconvolution of microdissected tissue showed enhanced activities of glial cell development and Delta-Notch signaling by increased p18. Remarkably, p18 upregulated Dlx2, which can subsequently induce olfactory bulb interneuron lineage while reducing upper-layer neurons and astrocytes. Together, our results demonstrated the potency of CDKIs in sequentially determining the boundaries among different cellular lineages arising from NSCs in the dorsal cortex.