Nuclear receptor NR5A2 controls neural stem cell fate decisions during development

Athanasios Stergiopoulos,Panagiotis K Politis

doi:10.1038/ncomms12230

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.

Highlights

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)
Here we report for the first time the identification of nuclear receptor NR5A2 as a key node in the gene regulatory networks that control NSC differentiation
Enough, NR5A2 was detected in high levels in bIII-Tubulin þ and NeuN þ neurons of the mantle zone (MZ) in early neural tube (E10.5 and E12.5) and, more weakly, in a subset of Nestin þ NSCs or Pax[6] þ neuronal progenitors of the ventricular zone (VZ) (Fig. 1e–k,o)

Summary

Introduction

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). Identification of novel players in the control of cell-cycle exit and differentiation of neural stem/progenitor cells (NSCs), may allow new therapeutic approaches, and provide mechanistic insights in nervous system formation and function. In this regard, here we report for the first time the identification of nuclear receptor NR5A2 ( known as LRH1) as a key node in the gene regulatory networks that control NSC differentiation. Later on during organogenesis and tissue homeostasis, NR5A2 is involved in promoting proliferation of progenitors and cancer cells from various tissues[11,12,13,14,15] Despite these effects, NR5A2 has not been previously correlated with nervous system development or function. We describe a new mechanism in the regulation of neurogenesis during CNS development that may allow novel approaches in neuro-regeneration

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Conclusion