EZH2 influences mdDA neuronal differentiation, maintenance and survival

Abstract

Over the last decade several components have been identified to be differentially expressed in subsets of mesodiencephalic dopaminergic (mdDA) neurons. These differences in molecular profile have been implied to be involved in the selective degeneration of the SNc neurons in Parkinson's disease. The emergence and maintenance of individual subsets is dependent on different transcriptional programs already present during development. In addition to the influence of transcription factors, recent studies have led to the hypothesis that modifications of histones might also influence the developmental program of neurons. In this study we focus on the histone methyltransferase EZH2 and its role in the development and maintenance of mdDA neurons. We generated two different conditional knock out (cKO) mice; an En1Cre driven cKO, for deletion of Ezh2 in mdDA progenitors and a Pitx3Cre driven cKO, to study the effect of post-mitotic deletion of Ezh2 on mdDA neurons maturation and neuronal survival. During development Ezh2 was found to be important for the generation of the proper amount of TH+ neurons. The loss of neurons primarily affected a rostrolateral population, which is also reflected in the analysis of the subset marks, Ahd2 and Cck. In contrast to early genetic ablation, post-mitotic deletion of Ezh2 did not lead to major developmental defects at E14.5. However, in 6 months old animals Cck was found ectopically in the rostral domain of mdDA neurons and Ahd2 expression was reduced in more mediocaudal positioned cells. In addition, Pitx3Cre driven deletion of Ezh2 led to a progressive loss of TH+ cells in the VTA and these animals display reduced climbing behavior. Together, our data demonstrates that Ezh2 is important for the generation of mdDA neurons during development and that during adult stages Ezh2 is important for the preservation of proper neuronal subset identity and survival.

Adolescent oxycodone exposure inhibits withdrawal‐induced expression of genes associated with the dopamine transmission

“…Opioid‐induced withdrawal is also associated with Ezh2 (enhancer of zester homolog 2) expression, which catalyzes H3K27me3 36 . Virally mediated overexpression of Ezh2 in the VTA represses genes for dopaminergic neuron survival and enhances morphine CPP 17 . We propose that prolonged exposure to oxycodone during adolescence increases the sensitivity to morphine later in adulthood via the suppression of adaptive gene expression.…”

Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids

“…The highest expression of the Enhancer of zeste homolog 2 (EZH2) was found in NSCs, and the lowest expression was found in Mat organoids. EZH2 involved in stem cell renewal and maintenance is highly expressed in NSCs or progenitor cells of the cortex, but its expression decreases in differentiated neurons [39][40][41] . The expression of CDH1-a co-factor that is required for the regulation of cortical neurogenesis and survival 42 -was noticeably higher in the BEM group than in other groups.…”

The role and mechanisms of polycomb repressive complex 2 on the regulation of osteogenic and neurogenic differentiation of stem cells

“…And EZH2 is abundantly expressed in immature neurons, whereas its expression significantly reduced during the maturation of hippocampal neurons 93 . Moreover, EZH2 regulates the generation of mesodiencephalic dopaminergic (mdDA) neuron and maintains the proper subset identity and the survival of different mdDA neurons during neural development 94,95 . Knockdown of EZH2 effectively promotes mdDA neuronal differentiation during midbrain development 96 .…”

“…SOX19b knockdown decreases the EZH2 upsurge and H3K27me3 at the promoters of ASCL1a and NGN1 , thereby reducing NSCs proliferation and premature differentiation into neurons 100 . The selective EZH2 inhibitor EPZ005687 effectively reduces the H3K27me3 level in ventral midbrain‐derived NSCs (VM‐NSCs) and enhances its differentiation into mdDA neurons 95 . A study has reported a crosstalk between RNA m6A modification and histone modifications.…”

“…93 Moreover, EZH2 regulates the generation of mesodiencephalic dopaminergic (mdDA) neuron and maintains the proper subset identity and the survival of different mdDA neurons during neural development. 94,95 Knockdown of EZH2 effectively promotes mdDA neuronal differentiation during midbrain development. 96 Conditional knockout of EZH2 produces ectopic mdDA neurons in the isthmic organizer (IsO) of mice hindbrain.…”