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Abstract
During midbrain development, dopamine neuron differentiation occurs before birth. Epigenetic processes such as DNA methylation and demethylation as well as post-translational modification of histones occur during neurogenesis. Here, we administered histamine (HA) into the brain of E12 embryos in vivo and observed significant lower immunoreactivity of Lmx1a+ and Tyrosine Hydroxylase (TH)+ cells, with parallel decreases in the expression of early (Lmx1a, Msx1) and late (Th) midbrain dopaminergic (mDA) genes. With MeDIP assays we found that HA decreases the percentage of 5-methylcytosine of Pitx3 and Th, without changes in 5-hydroxymethylcytosine. Additionally, HA treatment caused a significant increase in the repressive epigenetic modifications H3K9me3 in Pitx3 and Th, and also more H3K27me3 marks in Th. Furthermore, HA has a long-term effect on the formation of the nigrostriatal and mesolimbic/mesocortical pathways, since it causes a significant decrease in midbrain TH immunoreactivity, as well as alterations in dopaminergic neuronal fibers, and significant lower TH-positive area in the forebrain in whole-mount stainings. These findings suggest that HA diminishes dopaminergic gene transcription by altering several epigenetic components related to DNA and histone modifications, which affects mDA neuron progression during development.
Highlights
Midbrain dopaminergic neurons are essential for motor function control as well as for the regulation of reward and emotions (van Heesbeen et al, 2013)
We performed in utero microinjections of HA or vehicle, into the ventricular lumen close to the MB of E12 rat embryos, allowing them to develop to E14
Because it was previously reported that intrauterine injection of HA at E12 precludes Midbrain dopaminergic (mDA) differentiation at E14 (Escobedo-Avila et al, 2014), we quantified the immunoreactivity of Tyrosine Hydroxylase (TH) and Lmx1a in vehicleor HA-injected embryos, confirming a significant decrease in TH (Figure 1A)
Summary
Midbrain dopaminergic (mDA) neurons are essential for motor function control as well as for the regulation of reward and emotions (van Heesbeen et al, 2013). Dopaminergic neural progenitors express specific genes such as Lmx1a/b, Foxa, Msx1/2, and Ngn (Ang, 2006; Gale and Li, 2008; Nakatani et al, 2010; Yan et al, 2011). At this stage neural progenitors acquire mDA neuronal fate and start the last stage to become post-mitotic neurons (Yi et al, 2014). Differentiated mDA neurons extend their axons to reach the striatum (ST) and release dopamine to regulate motor function in the basal ganglia (Hegarty et al, 2013)
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