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Epigenetic regulation in (mid)brain development

By S. Mesman

Abstract

During embryonic development embryonic stem cells (ESCs) become committed to numerous cell-fates and can differentiate in neuronal stem cells (NSCs), which can convert into three different cell-types of the nervous system, neurons, astrocytes, and oligodendrocytes. During this differentiation genes are subject to a massive change in expression. The change in gene expression during development is controlled in many different ways, of which epigenetic control is importantly involved in cell-lineage specification and differentiation into different neuronal subsets. Many genes involved in brain development, like bdnf, dlk1, grb10, and dnmt1, 3a and 3b, are epigenetically controlled or control epigenetic changes, either by imprinting, which is a static epigenetic modification, or dynamic modifications on the chromatin. These epigenetic modifications can affect the DNA, methylation and non-coding (nc)RNAs binding gene promoters, the histones, which includes methylation and acetylation, and other parts of the transcriptional machinery, ncRNAs affecting transcript concentrations within the cell. Interplay is present between the epigenetic mechanisms intra- and intercellular, which guide the development of the neuronal precursors. Without such a tight regulation in gene expression neuronal development goes astray and neurological disorders submerge. Here an overview is given of known epigenetic changes in neurogenesis and gliogenesis during brain development. This review specifically focuses on the development of a particular brain area, namely the mesodiencephalic dopaminergic area. Much research is conducted at the moment to this brain area, since it is typically affected in Parkinson’s disease (PD). In PD massive neurodegeneration can be detected in the dopaminergic neurons of the substantia nigra, whereas the ventral tegmental area is less affected. This underscores the idea of the existence of different neuronal subsets which all rely on different molecular coding during development. Some of the specific gene expression in these neurons is thought to depend on epigenetic changes. Here a model is proposed in which the expression of tyrosine hydroxylase (TH), a dopaminergic marker, is dependent on epigenetic changes after signalling of neuronal growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derives neurotrophic factor (GDNF). This model further proposes the involvement of epigenetic changes in the development of specific dopaminergic subsets. Since it is known that dlk1 inhibits the expression of Dat and that neurons of the SNc do express the dopamine transporter Dat, but neurons of the VTA do not, Dlk1 is suggested to be involved in the development of these two neuronal subsets

Topics: Epigenetic regulation, brain development, BDNF, GDNF, mesodiencephalic dopaminergic system, Dlk1, substantia nigra, ventral tegmental area
Year: 2011
OAI identifier: oai:dspace.library.uu.nl:1874/210899
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