Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development.

During mammalian neocortical development, neural stem/progenitor cells (NSCs) sequentially give rise to deep layer neurons and superficial layer neurons through mid- to late-embryonic stages, shifting to gliogenic phase at perinatal stages. Previously, we found that the Hes genes inhibit neuronal differentiation and maintain NSCs. Here, we generated transgenic mice that overexpress Hes5 in NSCs of the central nervous system, and found that the transition timing from deep to superficial layer neurogenesis was shifted earlier, while gliogenesis precociously occurred in the developing neocortex of Hes5-overexpressing mice. By contrast, the transition from deep to superficial layer neurogenesis and the onset of gliogenesis were delayed in Hes5 knockout (KO) mice. We found that the Hmga genes (Hmga1/2) were downregulated in the neocortical regions of Hes5-overexpressing brain, whereas they were upregulated in the Hes5 KO brain. Furthermore, we found that Hes5 expression led to suppression of Hmga1/2 promoter activity. These results suggest that Hes5 regulates the transition timing between phases for specification of neocortical neurons and between neurogenesis and gliogenesis, accompanied by alteration in the expression levels of Hgma genes, in mammalian neocortical development.