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Review
. 2019 Apr;149(1):12-26.
doi: 10.1111/jnc.14601. Epub 2018 Nov 22.

Epigenetic cues modulating the generation of cell-type diversity in the cerebral cortex

Nicole Amberg  1 , Susanne Laukoter  1 , Simon Hippenmeyer  1
Affiliations
Review

Epigenetic cues modulating the generation of cell-type diversity in the cerebral cortex

Nicole Amberg et al. J Neurochem. 2019 Apr.

Abstract

The cerebral cortex is composed of a large variety of distinct cell-types including projection neurons, interneurons, and glial cells which emerge from distinct neural stem cell lineages. The vast majority of cortical projection neurons and certain classes of glial cells are generated by radial glial progenitor cells in a highly orchestrated manner. Recent studies employing single cell analysis and clonal lineage tracing suggest that neural stem cell and radial glial progenitor lineage progression are regulated in a profound deterministic manner. In this review we focus on recent advances based mainly on correlative phenotypic data emerging from functional genetic studies in mice. We establish hypotheses to test in future research and outline a conceptual framework how epigenetic cues modulate the generation of cell-type diversity during cortical development.

Keywords: cell-type diversity; cerebral cortex; gliogenesis; lineage progression; neurogenesis; radial glial progenitor cells.

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Figures

Figure 1
Figure 1
Epigenetic regulation of RGP‐mediated generation of cell‐type diversity. (a) Lineage instruction: epigenetic factors in RGPs together with local factors work in an orchestrated manner to instruct distinct neuronal/glial fates. These factors act only at a specific time window and during a distinct step of cell‐type generation. (b) Lineage pre‐priming: the entire RGP lineage is pre‐primed by a specific epigenetic factor in early RGPs throughout the course of development. However, the functional impact manifests only at a later stage of lineage progression (e.g. during glial differentiation or adult NSC proliferation). (c) Lineage priming: the entire lineage is instructed by the functional impact of an epigenetic factor that is uniformly present throughout all stages of development. In combination with local niche‐derived factors the epigenetic mark exerts its function on progenitor state, RGP proliferation and the entire successive lineage.
Figure 2
Figure 2
Epigenetic factors and modifications regulating the generation of cell‐type diversity during RGP lineage progression. High content of repressive H3K9me2/me3 and H3K27me3 marks and the presence of chromatin regulators such as BAF170, BRG1, CHD2, Pnky, TET1/3 and CTCF regulate stem cell maintenance and RGP self‐renewal while suppressing genes involved in neuron differentiation. For neuron production, repressive marks are replaced by active marks such as H3K4me3 or histone acetylation to promote expression of proneural genes mediating neuronal differentiation and maturation. Transition from repressive to activating epigenetic regulation is mediated through BAF155, BRN1, CHD5/8 and CBP. PRC and histone acetylation are essential for mediating the neurogenic to gliogenic transition. Adult NSCs display high levels of H3K27me3 and require the accumulation of H3K4me3 and expression of DNMT1, HDAC3, and CDKN1C for the faithful generation of OB inhibitory neurons. BAF, Brahma‐associated factor; Cdkn1c, cyclin‐dependent kinase inhibitor 1c; CHD, chromodomain‐helicase‐DNA‐binding; CTCF, CCCCTC‐binding factor; DNMT, DNA methyltransferase; HDAC, histone deacetylase, NSCs, neural stem cell; PRC, polycomb repressive complex; RGP, radial glial progenitor; TET, ten‐eleven translocation protein.
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