EZH2 regulates neuroepithelium structure and neuroblast proliferation by repressing p21

Abstract

The function of EZH2 as a transcription repressor is well characterized. However, its role during vertebrate development is still poorly understood, particularly in neurogenesis. Here, we uncover the role of EZH2 in controlling the integrity of the neural tube and allowing proper progenitor proliferation. We demonstrate that knocking down the EZH2 in chick embryo neural tubes unexpectedly disrupts the neuroepithelium (NE) structure, correlating with alteration of the Rho pathway, and reduces neural progenitor proliferation. Moreover, we use transcriptional profiling and functional assays to show that EZH2-mediated repression of p21WAF1/CIP1 contributes to both processes. Accordingly, overexpression of cytoplasmic p21WAF1/CIP1 induces NE structural alterations and p21WAF1/CIP1 suppression rescues proliferation defects and partially compensates for the structural alterations and the Rho activity. Overall, our findings describe a new role of EZH2 in controlling the NE integrity in the neural tube to allow proper progenitor proliferation.

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

“…p21 , a key cell cycle inhibitor and age‐associated negative regulator of NSPC proliferation (Akizu et al., 2016), was upregulated in Dbx2 ‐NSPCs (Figure 6i) as were Itgb5 , Dll4 and Gfap (Figure 6j–l). Conversely, Prrx1 , Igf2bp2 and Sox2 were downregulated in Dbx2 ‐NSPCs (Figure 6l–n), which is a change that is consistent with the positive influence of these genes on NSPC proliferation (Fujii, Kishi & Gotoh, 2013; Nishino, Kim, Zhu, Zhu & Morrison, 2013; Shimozaki, Clemenson & Gage, 2013).…”

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

“…Embryo developmental stage was determined following HH (59). Embryos were electroporated with the indicated DNAs at 3 μg/μL with 50 ηg/mL of Fast Green as previously described (54,60). Expanded protocol is described in SI Appendix, Materials and Methods.…”

Histone Lysine Methylation and Neurodevelopmental Disorders

“…Several studies have shown that EZH2 deficiencies in animal models induced abnormal neurogenesis in the cerebral cortex [ 106 ], cerebellum [ 107 ], and spinal cord [ 108 ] during embryonic development. Moreover, EZH2 is also implicated in adult hippocampal neurogenesis [ 109 ].…”

“…Moreover, EZH2 is also implicated in adult hippocampal neurogenesis [ 109 ]. The alteration of neurogenesis induced by EZH2 deficiencies has been associated with various neurogenic processes, such as the reduction of neural progenitor cell proliferation [ 108 , 109 , 110 ], cell fate change [ 106 , 107 , 111 , 112 , 113 ], and neuronal migration [ 114 , 115 , 116 ]. These results suggest that EZH2-induced H3K27 methylation plays an important role in various processes of neurodevelopment, dysfunction of which might be closely related to intellectual disability in patients with WVS.…”