Journal
MOLECULAR NEUROBIOLOGY
Volume 58, Issue 5, Pages 1952-1962Publisher
SPRINGER
DOI: 10.1007/s12035-020-02222-8
Keywords
Adult neural stem cells; LRH1; Prox1; Neuronal maturation; Dentate gyrus; Hippocampal neurogenesis
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Funding
- European Union (European Social Fund-ESF) through the Operational Programme Human Resources Development, Education and Lifelong Learning [MIS-5000432]
- Fondation Sante grant
- Hellenic Foundation for Research and Innovation (H.F.R.I) [1782]
- State Scholarships Foundation (IKgamma) PhD studentship
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NR5A2 is differentially expressed in the dentate gyrus of the adult hippocampus, with higher levels in neurons compared to adult neural stem/progenitor cells. Overexpression of NR5A2 induces the expression of Prox1 and promotes neuronal differentiation and axon outgrowth. Depletion of NR5A2 results in reduced number of neurons, highlighting its regulatory role in adult hippocampal neurogenesis.
Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is actively involved in brain homeostasis. Thus, identification of novel regulators in adult neurogenesis could significantly contribute to new therapies. We have recently unraveled the regulatory role of NR5A2 (also known as LRH1), a druggable orphan nuclear receptor, in embryonic neurogenesis. However, its involvement in adult neurogenesis is still an open question. Here we show that NR5A2 is differentially expressed in the DG of the adult hippocampus with neurons exhibiting higher levels of expression than adult neural stem/progenitor cells (aNSCs), suggesting a correlation with neuronal differentiation. Notably, NR5A2 overexpression in ex vivo cultured aNSCs induces expression of Prox1, a critical regulator of adult hippocampal neurogenesis. In agreement, NR5A2 is sufficient to reduce proliferation, increase neuronal differentiation, and promote axon outgrowth. Moreover, depletion of NR5A2 in DG cells in vivo caused a decrease in the number of NeuN as well as Calbindin-positive neurons, indicating its necessity for the maintenance of neuronal identity. Our data propose a regulatory role of NR5A2 in neuronal differentiation and fate specification of adult hippocampal NSCs.
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