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Nuclear Receptor NR5A2 Promotes Neuronal Identity in the Adult Hippocampus

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Abstract

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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Acknowledgments

We would like to thank Daphne Antoniou, Valeria Kaltezioti, Aristidis Charonis Elpinickie Ninou, and Artemis Michail for useful discussions and advices. We also thank Apostolos Klinakis and Evangelia Chavdoula for providing Adeno-Cre viruses, Pavlos Alexakos for help and guidance with animal handling, and Stamatis Pagakis and Biological Imaging Unit of BRFAA for help and guidance in image analysis.

Funding

This research is co-financed by Greece and the European Union (European Social Fund—ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by a State Scholarships Foundation (ΙΚΥ) PhD studentship to MT. This research work was also supported by Fondation Sante grant and the Hellenic Foundation for Research and Innovation (H.F.R.I) under the “First Call for H.F.R.I Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 1782) to PKP.

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Authors and Affiliations

  1. Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece

    Matina Tsampoula, Isaak Tarampoulous, Ivi Antoniadou, Dimitrios Gkikas, Kostas Vekrellis & Panagiotis K Politis

  2. Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece

    Yassemi Koutmani

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  1. Matina Tsampoula
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Correspondence to Panagiotis K Politis.

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The experimental protocols were approved by the ethics committee (Athens Prefecture Veterinarian Service; K/3237/11-05-2012) and performed in the Center of Experimental Surgery of the Biomedical Research Foundation of the Academy of Athens. Mice were treated according to the standards of the animal practice of the Office of Laboratory Animal Welfare-NIH and Greek animal welfare bodies.

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Supplementary Figure 1.

Negative control for NR5A2 immunostainings. Immunostaining against NR5A2 on the 8-week-old murine DG without primary antibody. Cell nuclei were labelled with DAPI (blue). Scale bar, 250 μm (PNG 2062 kb).

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Tsampoula, M., Tarampoulous, I., Antoniadou, I. et al. Nuclear Receptor NR5A2 Promotes Neuronal Identity in the Adult Hippocampus. Mol Neurobiol 58, 1952–1962 (2021). https://doi.org/10.1007/s12035-020-02222-8

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