Tip60/KAT5 histone acetyltransferase is required for maintenance and neurogenesis of embryonic neural stem cells

Epigenetic regulation via epigenetic factors in collaboration with tissue specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors which are coordinately activated or inactivated during the processes and their dysregulation is linked to brain abnormality and intellectual disability. However, precise mechanism of epigenetic regulation in brain development and neurogenesis is still largely unknown. Here, we show that Tip60/KAT5 deletion in neural stem and progenitor cells (NSPCs) in mouse results in multiple abnormalities of brain development. Tip60 deficient embryonic brain was microcephaly and proliferating cells in developing brain was reduced by Tip60 deficiency. Neural differentiation and neural migration were also severely affected in Tip60 deficient brains. Interestingly, gliogenesis following neurogenesis in developing brains was started from earlier stage of development in Tip60 deficient brains, suggesting that Tip60 is involved in switching from neurogenesis to gliogenesis in brain development. It was also confirmed that poor neurosphere formation, proliferation defect, neural differentiation defect, and accelerating astrocytic differentiation in mutant NSPCs derived from Tip60 deficient embryonic brains. This study uncovers a critical role of Tip60 in brain development and NSPC maintenance and function in vivo and in vitro.