Ezh2 Regulates Dopaminergic Neurons Development In Midbrain And Neurogenesis In Adult Mice Through Modifying H3K27me3

Midbrain dopaminergic(mDA)neurons play an important role in regulation of voluntary movement,cognition and emotional behavior.Studies on the development of mDA neurons will contribute to the diagnosis and treatment of Parkinson’s s disease(PD),schizophrenia(Schizophrenia),and depression(Depression)and other related neurological diseases.The generation of mDA neurons results from a precise transcription regulation.Enhancer of zeste homolog 2(Ezh2)is the core component of Polycomb Repressive Complex 2(PRC2),and it is responsible for trimethylation of H3 Lys 27(H3K27me3).H3K27me3 recruits inhibitory factors like PRC1 as a docking site and represses the expression of gene by changing chromatin structure.Previous studies showed that H3K27me3 increased with prolonged incubation in ventral midbrain derived neural stem cells(VM-NSCs).However,high dose ascorbic acid promotes VM-NSCs differentiation into dopaminergic neurons through facilitating the expression of Jmjd3 and Tet1 with loss of H3k27m3 and gain of 5hmC.The contribution of H3K27me3 to the development of mDA neurons is still unclear.Our investigation revealed that Ezh2 gradually decreased in developing midbrain.The decline of Ezh2 reduced H3K27me3 and promoted the differentiation of mDA neurons.The selective inhibitor of Ezh2 EPZ005687 repressed the proliferation of VMNSCs and increased the differentiation of mDA neurons.Inhibition of Ezh2 promoted the expression of mDA neurons developmental regulators,including FoxA2,Nurr1,Wnt1 a,and Wnt5 a.We also showed that upregulated Nurr1 is essential for the differentiation of mDA neurons through inhibition of Ezh2.These findings support an important role of Ezh2 in the development of mDA neurons.Adult neural stem cells(aNSCs)can be self-renewal and have the capacity to differentiation into neurons and gila.The role of Ezh2 on the proliferation or differentiation of aNSCs still remains unclear.We found that EPZ005687 treatment promoted cell proliferation and facilitated NSCs differentiation into neurons in NSCs cultures.Moreever,EPZ005687 enhanced neurogenesis in subventricular zone and dentate gyrus in adult C57BL/6 mice.BDNF,The mRNA levels of GDNF,Wnt3 a and Wnt5 a were up-regulated in EPZ005687-treated NSCs cultures.With Wnt/β-catenin signal inhibitor treatment,the effect of Ezh2 inhibition-mediated neurogenesis was blocked.Besides,anti-Wnt5 a repressed Ezh2 inhibition-mediated cell proliferation in NSCs cultures.These findings indicate that Ezh2 paly an important role in neurogenesis and cell proliferation.