Abstract
Epigenetic regulatory complexes play key roles in the modulation of transcriptional regulation underlying neural stem cell (NSC) proliferation and progeny specification. How specific cofactors guide histone demethylase LSD1/KDM1A complex to regulate distinct NSC-related gene activation and repression in cortical neurogenesis remains unclear. Here we demonstrate that Rcor2, a co-repressor of LSD1, is mainly expressed in the central nervous system (CNS) and plays a key role in epigenetic regulation of cortical development. Depletion of Rcor2 results in reduced NPC proliferation, neuron population, neocortex thickness and brain size. We find that Rcor2 directly targets Dlx2 and Shh, and represses their expressions in developing neocortex. In addition, inhibition of Shh signals rescues the neurogenesis defects caused by Rcor2 depletion both in vivo and in vitro. Hence, our findings suggest that co-repressor Rcor2 is critical for cortical development by repressing Shh signalling pathway in dorsal telencephalon.
Highlights
Epigenetic regulatory complexes play key roles in the modulation of transcriptional regulation underlying neural stem cell (NSC) proliferation and progeny specification
Sonic hedgehog (Shh) expression is first observed in the mesendoderm and diencephalon between E8.5 and E9 during telencephalic development, which are restricted to the Medial Ganglionic Eminence (MGE) and preoptic area (PoA) by E9.5 and by E12.5, respectively, to pattern the ventral brain, while maintaining a very low activity in the developing dorsal cortex[15,16,17,18,19]
To examine the endogenous Rcor[2] expression pattern during cortical development, we performed in situ hybridization and immunostaining by an RNA probe or antibody, and both were specific by no signals detected in the neural lineage-knockout Rcor2fl/ flNesCre (Rcor2cko) cortex (Supplementary Fig. 1b,c)
Summary
Epigenetic regulatory complexes play key roles in the modulation of transcriptional regulation underlying neural stem cell (NSC) proliferation and progeny specification. Multiple studies exploring the mechanism of temporal and spatial regulation that lead to the remarkable cellular diversity of the mature neocortex have underlined the importance of organizing signals such as Sonic hedgehog (Shh), fibroblast growth factors, WNTs, and bone morphogenetic proteins, which provide positional information in body axes[7,9,10,11,12,13,14] Among these signals, Shh expression is first observed in the mesendoderm and diencephalon between E8.5 and E9 during telencephalic development, which are restricted to the Medial Ganglionic Eminence (MGE) and PoA by E9.5 and by E12.5, respectively, to pattern the ventral brain, while maintaining a very low activity in the developing dorsal cortex[15,16,17,18,19]. The disruption of Shh, the direct regulation target of Rcor[2] and upstream effector of Dlx[2], rescues the neurogenesis defects caused by Rcor[2] depletion, suggesting that Rcor[2] plays a critical role of temporal and spatial regulation of gene expressions to safeguard cortical neurogenesis in brain development
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