The Neurodevelopmental Disorders Associated Gene Rnf113a Regulates Survival and Differentiation Properties of Neural Stem Cells.

RNF113A (Ring Finger Protein 113A) is genetically associated with autism spectrum disorders and X-linked trichothiodystrophy (TTD) syndrome. Loss-of-function mutations in human RNF113A are causally linked to TTD, which is characterized by abnormal development of the central nervous system (CNS) and mental retardation. How the loss of RNF113A activity affects brain development is not known. Here we identify Rnf113a1 as a critical regulator of cell death and neurogenesis during mouse brain development. Rnf113a1 gene exhibits widespread expression in the embryonic CNS. Knockdown studies in embryonic cortical neural stem/progenitor cells (NSCs) and the mouse cortex suggest that Rnf113a1 controls the survival, proliferation, and differentiation properties of progenitor cells. Importantly, Rnf113a1 deficiency triggers cell apoptosis via a combined action on essential regulators of cell survival, including p53, Nupr1, and Rad51. Collectively, these observations establish Rnf113a1 as a regulatory factor in CNS development and provide insights into its role in neurodevelopmental defects associated with TTD and autism.

Nuclear Receptor NR5A2 Promotes Neuronal Identity in the Adult Hippocampus.

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.