[en] Long-term maintenance of the adult neurogenic niche depends on proper regulation of entry and exit from quiescence. Neural stem cell (NSC) transition from quiescence to activation is a complex process requiring precise cell-cycle control coordinated with transcriptional and morphological changes. How NSC fate transitions in coordination with the cell-cycle machinery remains poorly understood. Here we show that the Rb/E2F axis functions by linking the cell-cycle machinery to pivotal regulators of NSC fate. Deletion of Rb family proteins results in activation of NSCs, inducing a transcriptomic transition toward activation. Deletion of their target activator E2Fs1/3 results in intractable quiescence and cessation of neurogenesis. We show that the Rb/E2F axis mediates these fate transitions through regulation of factors essential for NSC function, including REST and ASCL1. Thus, the Rb/E2F axis is an important regulator of NSC fate, coordinating cell-cycle control with NSC activation and quiescence fate transitions.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Fong, Bensun C; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Chakroun, Imane; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Iqbal, Mohamed Ariff; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Paul, Smitha; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Bastasic, Joseph; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
O'Neil, Daniel; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Yakubovich, Edward; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Bejjani, Anthony T; Department of Biology, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
Ahmadi, Nastaran; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Carter, Anthony; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Clark, Alysen; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Leone, Gustavo; MCW Cancer Centre, Medical College of Wisconsin, Milwaukee, WI, USA
Park, David S; Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 4N1, Canada, Department of Cell Biology, University of Calgary, Calgary, AB T2N 4N1, Canada, Department of Anatomy, University of Calgary Calgary AB T2N 4N1 Canada
Ghanem, Noël; Department of Biology, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
Vandenbosch, Renaud ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Slack, Ruth S; University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: rslack@uottawa.ca
This work was supported by core facilities at the University of Ottawa, including Surgical Core; Dr. Vera Tang, Flow Cytometry and Virometry Core; Cell Biology and Image Acquisition Core; facilities at the Ottawa Hospital Research Institute, including the Flow Cytometry and Cell Sorting Facility and StemCore Laboratories; and The Centre for Applied Genomics at The Hospital for Sick Children , Toronto. This work was funded by CIHR grants (to R.S.S.); Belgian National Funds for Scientific Research (FRS-FNRS, Belgium), the Fondation Léon Fredericq (ULiège, Belgium), the Fonds spéciaux (ULiège, Belgium) (to R.V.); the University Research Board, American University of Beirut ( URB ), the Mamdouha El-Sayed Bobst Deanship Fund ( FAS ) at American University of Beirut ( AUB ), and the Lebanese National Council for Scientific Research ( CNRS-L ) (to N.G.); and an Ontario Graduate Scholarship (to B.C.F.).
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