title: Nuclear receptor NR5A2 controls neural stem cell fate decisions during development.
abstract: The enormous complexity of mammalian central nervous system (CNS) is generated by highly synchronized actions of diverse factors and signalling molecules in neural stem/progenitor cells (NSCs). However, the molecular mechanisms that integrate extrinsic and intrinsic signals to control proliferation versus differentiation decisions of NSCs are not well-understood. Here we identify nuclear receptor NR5A2 as a central node in these regulatory networks and key player in neural development. Overexpression and loss-of-function experiments in primary NSCs and mouse embryos suggest that NR5A2 synchronizes cell-cycle exit with induction of neurogenesis and inhibition of astrogliogenesis by direct regulatory effects on Ink4/Arf locus, Prox1, a downstream target of proneural genes, as well as Notch1 and JAK/STAT signalling pathways. Upstream of NR5a2, proneural genes, as well as Notch1 and JAK/STAT pathways control NR5a2 endogenous expression. Collectively, these observations render NR5A2 a critical regulator of neural development and target gene for NSC-based treatments of CNS-related diseases.
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27 Athens, Greece.
authors.forename: Athanasios
authors.identifier: 0000-0002-7908-0669
authors.initials: A
authors.lastname: Stergiopoulos
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27 Athens, Greece.
authors.forename: Panagiotis K
authors.identifier: 0000-0002-2556-2857
authors.initials: PK
authors.lastname: Politis
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002490:Central Nervous System / Q000196:embryology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018398:Homeodomain Proteins; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D050791:STAT Transcription Factors; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D020727:ADP-Ribosylation Factors