Epigenetic mechanisms in the development and maintenance of dopaminergic neurons

Abstract

SummaryMesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies. Key words: Brain, Development, Dopamine, Epigenetics, Gene regulation, Midbrain IntroductionIf you turn this page, both the decision you make and the action that you carry out are significantly influenced by the amount of dopamine (DA; see Glossary, Box 1) released from dopaminergic neurons within your brain. Mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra pars compacta (SNc; see Glossary, Box 1), in particular, are essential for motor functions whereas mdDA neurons of the ventral tegmental area (VTA; see Glossary, Box 1) and the retrorubal field (RRF; see Glossary, Box 1) are involved in the regulation of emotions and reward . Notably, severe loss of SNc mdDA neurons is a pathological hallmark of Parkinson's disease (PD) (Sulzer, 2007). By contrast, mdDA neurons in the VTA and RRF, which remain intact in PD, are part of the mesocorticolimbic system (see Glossary, Box 1), in which defective DA neurotransmission has been implicated in the development of drug addiction, depression and schizophrenia (Nestler, 2000). Given their involvement in neurodegenerative diseases and psychiatric disorders, mdDA neurons have been studied intensively in recent years.In the last two decades, a variety of molecular approaches have revealed factors that are specific for mdDA neuronal subsets or that guide their spatial organization ; recently, a pathway that molecularly distinguishes SNc DA neurons from those located in the VTA was identified (Jacobs et al., 2011). In addition to molecular profiling of DA neurons, however, a second level of complexity has been added by the rapidly emerging field of epigenetics, which has provided new insights into the origin and maintenance of distinctive gene expression patterns in mdDA neurons. Current definitions of epigenetics often emphasize the heritability of changes in gene expression throughout cell divisions that are not due to alterations in DNA sequence. However, perhaps a more appropriate definition of epigenetics, especially when applying this term to mature neurons that cannot divide, is postulated by Adrian Bird: 'The structural adaptation of chromosomal regio...

Lineage-Specific Regulation of Epigenetic Modifier Genes in Human Liver and Brain

“…SWI/SNF is one of the best described ATP-dependent chromatin-remodeling complexes and has many different targets and functions depending on the combinatorial assembly of its subunits [15]. Our data corroborated the known expression of SMARCA2 (also called BRM) in neurons [54] and in the liver [55]. In conclusion, data on EMG expression confirmed that the two in vitro cultures used here to represent the hepatic and neuronal lineage are more closely related to their respective primary cell types (huHep and Ctx) than to each other.…”

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

“…Re-activation of Nurr1 target genes in En1 -/-embryos by HDAC inhibition is analogous to the previously described upregulation of Th expression upon HDAC inhibition in Pitx3 gfp/-embryos (Jacobs et al, 2009a). Pitx3 crucially influences N-CoR2(Smrt)-Sin3-HDAC-mediated repression of mdDA genes by recruitment of the Nurr1-PSF transcriptional complex and release of Smrt-HDAC complexes (Jacobs et al, 2009a;Van Heesbeen et al, 2013). It has been shown that the N-CoR-Sin3-HDAC complex can be recruited to the Engrailed homology 1 domain (Eh1) of HesX1 (Dasen et al, 2001) and our finding that En1 can directly interact with PSF suggests that En1 releases HDAC-mediated repression in a similar manner to that described for Pitx3.…”

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

“…Jacobs and colleagues (Jacobs et al, 2009b) have reported another epigenetic control mechanism mediated by the Nurr1 activator Pitx3, in which Pitx3 potentiates Nurr1-induced DA gene expression by releasing an Smrt (Ncor1 -Mouse Genome Informatics)-mediated repressor complex (Smrt/Sin3a/Hdac). In addition, Nrsf (Rest -Mouse Genome Informatics) MeCP2 (Yang et al, 2011) have been suggested to be the central negative regulators of Th gene transcription during mDA neuron development, possibly by repressing Nurr1 actions (van Heesbeen et al, 2013). It remains to be seen whether all these repressor proteins form a large repressor complex, or if different combinations of the proteins are generated on different regions of the promoters or in different cellular contexts.…”