During development, neural stem cells (NSCs) give rise to the cellular diversity of the brain and nervous system. These cells persist into adulthood to act as a cellular reservoir, capable of maintaining the integrity of the networks, to which they gave rise. Despite their requirement for continued replenishment of the cells that comprise adult neural networks, the factors and mechanisms that regulate NSCs in vivo, remain poorly understood.
The MYST family histone acetyltransferase, KAT6B (MYST4, QKF) plays essential roles in the developing cortex and maintaining self-renewal and cell fate specification in adult NSCs of the subventricular zone (SVZ), with a progressive decrease in Kat6b gene activity observed as NSCs undergo differentiation. Mutations in the human KAT6B gene underlie intellectual disability disorders. Genitopatellar syndrome and the Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome result from heterozygous mutations in KAT6B. However, the mechanisms by which KAT6B impairment results in intellectual disability remain unknown.
Here, we demonstrate that KAT6B directs NSC proliferation and differentiation in vivo and in vitro. Cultured Kat6b–/– NSCs show impaired proliferation and reduced neurogenesis and neurite outgrowth. Conversely, Kat6b overexpression enhances NSC proliferation and neuronal differentiation in vitro. We show that KAT6B regulates key NSC pluripotency and neurogenesis pathways and identify KAT6B as a novel regulator of SOX family proteins, including SOX2. We demonstrate that Sox2 overexpression partially rescues the proliferation defect in Kat6b–/– NSCs.
Taken together, our results identify KAT6B as an essential facilitator of neurogenesis, upstream of the pioneer transcription factor SOX2.