The atypical CDK activator RingoA/Spy1 regulates exit from quiescence in neural stem cells
Laura Gonzalez,
Ana Domingo-Muelas,
Pere Duart-Abadia,
Marc Nuñez,
Petra Mikolcevic,
Elisabet Llonch,
Monica Cubillos-Rojas,
Begoña Cánovas,
Stephen M.A. Forrow,
Jose Manuel Morante-Redolat,
Isabel Fariñas,
Angel R. Nebreda
Affiliations
Laura Gonzalez
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Ana Domingo-Muelas
Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, 46100 Burjassot, Spain; Instituto de Biotecnología y Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid , Spain
Pere Duart-Abadia
Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, 46100 Burjassot, Spain; Instituto de Biotecnología y Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid , Spain
Marc Nuñez
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Petra Mikolcevic
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Elisabet Llonch
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Monica Cubillos-Rojas
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Begoña Cánovas
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Stephen M.A. Forrow
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Jose Manuel Morante-Redolat
Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, 46100 Burjassot, Spain; Instituto de Biotecnología y Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid , Spain
Isabel Fariñas
Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, 46100 Burjassot, Spain; Instituto de Biotecnología y Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid , Spain; Corresponding author
Angel R. Nebreda
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain; Corresponding author
Summary: In the adult mammalian brain, most neural stem cells (NSCs) are held in a reversible state of quiescence, which is essential to avoid NSC exhaustion and determine the appropriate neurogenesis rate. NSCs of the mouse adult subependymal niche provide neurons for olfactory circuits and can be found at different depths of quiescence, but very little is known on how their quiescence-to-activation transition is controlled. Here, we identify the atypical cyclin-dependent kinase (CDK) activator RingoA as a regulator of this process. We show that the expression of RingoA increases the levels of CDK activity and facilitates cell cycle entry of a subset of NSCs that divide slowly. Accordingly, RingoA-deficient mice exhibit reduced olfactory neurogenesis with an accumulation of quiescent NSCs. Our results indicate that RingoA plays an important role in setting the threshold of CDK activity required for adult NSCs to exit quiescence and may represent a dormancy regulator in adult mammalian tissues.
