PgmNr Z6257: A novel role for miR-9 and Argonaute proteins in balancing quiescent and activated neural stem cell states.

Authors:
M. Coolen 1 ; S. Katz 1 ; D. Cussigh 1 ; N. Urban 2 ; I. Blomfield 2 ; F. Guillemot 2 ; L. Bally-Cuif 1


Institutes
1) NEUROPSI CNRS, Gif-sur-Yvette, FR; 2) Francis Crick Institute, London, UK.


Abstract:

Adult neurogenesis is the process by which adult neural stem cells (NSCs) produce new neuronal and glial cells throughout an animal life. Over the past two decades, studies in vertebrate animal models have unveiled the crucial importance of this phenomenon for neural tissue homeostasis and proper brain function. Fundamentally, this process is a balance between maintaining a quiescent NSC pool and recruiting them into the neurogenesis cascade. Using the adult zebrafish telencephalon as a model, we aim at deciphering the molecular mechanisms governing this balance. We place special focus on microRNA-9 (miR-9), which we previously showed to control the transition between commitment states in embryonic neural progenitors. Our recent work shows that miR-9 expression in the adult telencephalon is restricted to NSC residing in a quiescent state (qNSCs) and is anchoring them in this state, at least in part through maintaining high levels of active Notch signaling. Moreover miR-9 expression highlights a striking heterogeneity within qNSCs, which we could link to the division history of the cells. Unexpectedly, we also could observe that miR-9 concentrates into the nucleus of qNSCs together with Argonaute proteins, effector proteins of microRNAs. Manipulating the subcellular localization of miR-9/Ago complexes impacts the quiescent vs activated state of NSCs, thus implying that miR-9 is regulating quiescence through a non-canonical nuclear activity. Interestingly, miR-9/Ago nuclear localization is a specificity of adult NSCs, as opposed to embryonic and juvenile NSCs, where we find it exclusively in the cytoplasm; it thus reveals and highlights a marked age-dependent change in NSCs properties and microRNA regulation.