The intricately orchestrated series of events in nervous system development begins with the formation of neuroepithelial stem cells. These cells proliferate, creating progenitor cells that ultimately form neurons and the glia that provide support and protection for neurons. The balance of neurons and glia is fundamental to the development of a healthy brain.
Achieving the optimal neuron–glia balance depends on a delicate relationship between the proliferation of progenitors and the differentiation of neurons and glia. While it is thought that repressors and the corepressors that bind to them affect this relationship, repressor/corepressor complexes have not been shown in vivo.
A team of researchers from OHSU’s Vollum Institute has now identified, in embryonic brains of mice, a repressor/corepressor complex consisting of Insulinoma-associated 1 (INSM1), which halts the cycle of cell division, and the RE1 Silencing Transcription factor (REST) corepressors RCOR1 and RCOR2. The findings were published in the Proceedings of the National Academy of Sciences on Jan. 3, 2017.
The research, led by Gail Mandel, Ph.D., senior scientist at the Vollum Institute, with OHSU graduate student Caitlin Monaghan as first author, identified for the first time a repressor complex required for these critical transcription events that lead to the cessation of neural proliferation and therefore enable the production of proper numbers of differentiated neurons and glia. The findings demonstrated that an INSM1/RCOR1/2 complex controls the balance of proliferation and differentiation during brain development. Eliminating either INSM1 or both RCOR1 and RCOR2 in the brains of mice significantly increased neural proliferation over differentiation of neurons and glia oligodendrocytes. The resulting abnormal brain morphology was restored when REST levels in the RCOR1/2-deficient brain normalized.
This research was supported by NIH grants NS022518, ULITR000128, NS093066, and DK09949. Other OHSU authors include Tamilla Nechiporuka from the Mandel lab, as well as Sophia Jeng and Shannon McWeeney from the Department of Medical Informatics and Clinical Epidemiology in the OHSU School of Medicine.