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.
Highlights
The Substantia Nigra pars compacta (SNc) and the ventral tegmental area (VTA) are two neuronal sub-populations of the mesodiencephalic dopaminergic system, that can already be distinguished during development (Smits et al, 2006; Veenvliet et al, 2013)
Previous studies have shown that the conditional deletion of Ezh2 in neuronal progenitors shift the balance between selfrenewal and differentiation, in favor of differentiation (Pereira et al, 2010; Zemke et al, 2015; Feng et al, 2016)
Enhancer of Zeste homolog 2 (EZH2) is the methyltransferase of PRC2, which catalyzes the methylation of H3K27 (Cao and Zhang, 2004b; Margueron et al, 2008; Shen et al, 2008) and in previous studies in which Ezh2 is conditionally removed from neuronal progenitors a widespread loss of H3K27me3 is observed (Hirabayashi et al, 2009; Pereira et al, 2010; Zemke et al, 2015)
Summary
The Substantia Nigra pars compacta (SNc) and the ventral tegmental area (VTA) are two neuronal sub-populations of the mesodiencephalic dopaminergic (mdDA) system, that can already be distinguished during development (Smits et al, 2006; Veenvliet et al, 2013). Epigenetics Influence Dopaminergic Neuronal Development (Prakash and Wurst, 2006; Veenvliet and Smidt, 2014) Even though both groups of neurons use dopamine (DA) as their neurotransmitters, they are molecular distinct and depend on unique transcriptional programs for their development and survival (Veenvliet and Smidt, 2014). Both subsets arise from the same progenitor pool under the influence of differentially expressed transcription factors like Pitx and En1 (Veenvliet et al, 2013; Panman et al, 2014). After the establishment of the SNc phenotype it is hypothesized that the remaining DA neurons acquire a VTA phenotype by default (Veenvliet et al, 2013; Panman et al, 2014)
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