Understanding neurogenesis in the developing mouse brain

Understanding neurogenesis in the developing mouse brain

Epigenetic regulatory complexes play key roles in the modulation of transcriptional regulation underlying neural stem cell (NSC) proliferation and progeny specification.

As the first identified RCOR protein, Rcor1 is widely studied in various types of cells, playing important roles in mouse erythropoiesis and neuronal or synaptic gene regulation by modifying chromatin configuration. Sharing 70% sequence similarities with Rcor1, Rcor2 can form a protein complex with LSD1, to facilitate its demethylase activity on nucleosome in embryonic stem cells (ESCs). Furthermore, Rcor2 but not Rcor1 has been described as a Sox2 substitute to regulate ESC proliferation and promote the formation of induced pluripotent stem cells34. However, the in vivo function of Rcor2 in development is unknown.

How specific cofactors guide histone demethylase LSD1/KDM1A complex to regulate distinct NSC-related gene activation and repression in cortical neurogenesis remains unclear.

Researchers demonstrate that Rcor2 is mainly expressed in the central nervous system (CNS) and affects NSC proliferation and neurogenesis during cortical development.

They find that Rcor2 associating with LSD1 plays a determinant role in directly binding to Dlx2 and Shh promoter regions, to inhibit gene expression. Depletion of Rcor2 results in reduced NPC proliferation, neuron population, neocortex thickness and brain size. Rcor2 directly targets Dlx2 and Shh, and represses their expressions in developing neocortex.

The disruption of Shh, the direct regulation target of Rcor2 and upstream effector of Dlx2, rescues the neurogenesis defects caused by Rcor2 depletion, suggesting that Rcor2 plays a critical role of temporal and spatial regulation of gene expressions to safeguard cortical neurogenesis in brain development.