The chromatin modifying complex CoREST/LSD1 negatively regulates notch pathway during cerebral cortex development.
The development of the cerebral cortex is a dynamic and coordinated process in which cell division, cell death, migration, and differentiation must be highly regulated to acquire the final architecture and functional competence of the mature organ. Notch pathway is an important regulator of differentiation and it is essential to maintain neural stem cell (NSC) pool. Here, we studied the role of epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and its interactor CoREST in the regulation of the Notch pathway activity during the development of the cerebral cortex. We found that CoREST and LSD1 interact in vitro with RBPJ-κ in the repressor complex and these proteins are released upon overexpression of Notch intracellular domain (NICD). We corroborated LSD1 and RBPJ-κ interaction in developing cerebral cortex and also found that LSD1 binds to the hes1 promoter. Knock-down of CoREST and LSD1 by in utero electroporation increases Hes1 expression in vivo and decreases Ngn2. Interestingly, we found a functional interaction between CoREST and LSD1 with Notch pathway. This conclusion is based on the observation that both the defects in neuronal migration and the increase in the number of cells expressing Sox2 and Tbr2 were associated to the knock-down of either CoREST or LSD1 and were reversed by the loss of Notch. These results demonstrate that CoREST and LSD1 downregulate the Notch pathway in the developing cerebral cortex, thus suggesting a role of epigenetic regulation in the fine tuning of cell differentiation. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1360-1373, 2016.
Faculty of Medicine, Program in Physiology and Biophysics, Institute for Biomedical Sciences, Universidad de Chile, Santiago, Chile.|Faculty of Medicine, Biomedical Neuroscience Institute (BNI), Universidad de Chile, Santiago, Chile.
Cecilia I
CI
Lopez
Faculty of Medicine, Program in Physiology and Biophysics, Institute for Biomedical Sciences, Universidad de Chile, Santiago, Chile.|Faculty of Medicine, Biomedical Neuroscience Institute (BNI), Universidad de Chile, Santiago, Chile.
Katherine E
KE
Saud
Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research and FONDAP Center for Genome Regulation, Universidad Andre's Bello, Santiago, Chile.
Rodrigo
R
Aguilar
Faculty of Medicine, Program in Physiology and Biophysics, Institute for Biomedical Sciences, Universidad de Chile, Santiago, Chile.|Faculty of Medicine, Biomedical Neuroscience Institute (BNI), Universidad de Chile, Santiago, Chile.
F Andrés
FA
Berndt
Faculty of Medicine, Program in Physiology and Biophysics, Institute for Biomedical Sciences, Universidad de Chile, Santiago, Chile.|Faculty of Medicine, Biomedical Neuroscience Institute (BNI), Universidad de Chile, Santiago, Chile.
José
J
Cánovas
Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research and FONDAP Center for Genome Regulation, Universidad Andre's Bello, Santiago, Chile.
Martín
M
Montecino
Faculty of Medicine, Program in Physiology and Biophysics, Institute for Biomedical Sciences, Universidad de Chile, Santiago, Chile.|Faculty of Medicine, Biomedical Neuroscience Institute (BNI), Universidad de Chile, Santiago, Chile.
Manuel
M
Kukuljan
D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D056970:Co-Repressor Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
D002843:Chromatin; D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; C121019:RCOR1 protein, human; D051880:Receptors, Notch; D056466:Histone Demethylases; C495195:KDM1A protein, human
cerebral cortex; development; differentiation; epigenetic; neurogenesis