Hbp1 regulates the timing of neuronal differentiation during cortical development by controlling cell cycle progression

Abstract

In the developing mammalian brain, neural stem cells (NSCs) initially expand the progenitor pool by symmetric divisions. NSCs then shift from symmetric to asymmetric division and commence neurogenesis. Although the precise mechanisms regulating the developmental timing of this transition have not been fully elucidated, gradual elongation in the length of the cell cycle and coinciding accumulation of determinants that promote neuronal differentiation might function as a biological clock that regulates the onset of asymmetric division and neurogenesis.We conducted gene expression profiling of embryonic NSCs in the cortical regions and found that expression of high mobility group box transcription factor 1 (Hbp1) was upregulated during neurogenic stages. Induced conditional knockout mice of Hbp1, generated by crossing with Nestin-CreERT2 mice, exhibited a remarkable dilatation of the telencephalic vesicles with a tangentially expanded ventricular zone and a thinner cortical plate containing reduced numbers of neurons. In these Hbp1-deficient mouse embryos, neural stem/ progenitor cells continued to divide with a shorter cell cycle length. Moreover, downstream target genes of the Wnt signaling, such as cyclin D1 (Ccnd1) and c-jun (Jun), were upregulated in the germinal zone of the cortical regions. These results indicate that Hbp1 plays a crucial role in regulating the timing of cortical neurogenesis by elongating the cell cycle and that it is essential for normal cortical development.