Mediator Med23 Regulates Adult Hippocampal Neurogenesis

Guo-Yan Chen; Shuai Zhang; Chong-Hui Li; Cong-Cong Qi; Ya-Zhou Wang; Jia-Yin Chen; Gang Wang; Yu-Qiang Ding; Chang-Jun Su

doi:10.3389/fcell.2020.00699

Mediator Med23 Regulates Adult Hippocampal Neurogenesis

Front Cell Dev Biol. 2020 Jul 29:8:699. doi: 10.3389/fcell.2020.00699. eCollection 2020.

Authors

Guo-Yan Chen^{1

2}, Shuai Zhang^{3

4}, Chong-Hui Li³, Cong-Cong Qi⁵, Ya-Zhou Wang⁶, Jia-Yin Chen², Gang Wang^{3

7}, Yu-Qiang Ding^{2

5}, Chang-Jun Su¹

Affiliations

¹ Department of Neurology, Tangdu Hospital, Air Force Medical University (Fourth Military Medical University), Xi'an, China.
² Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai, China.
³ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁴ School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China.
⁵ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, and Department of Laboratory Animal Science, Fudan University, Shanghai, China.
⁶ Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
⁷ School of Life Sciences, Fudan University, Shanghai, China.

Abstract

Mammalian Mediator (Med) is a key regulator of gene expression by linking transcription factors to RNA polymerase II (Pol II) transcription machineries. The Mediator subunit 23 (Med23) is a member of the conserved Med protein complex and plays essential roles in diverse biological processes including adipogenesis, carcinogenesis, osteoblast differentiation, and T-cell activation. However, its potential functions in the nervous system remain unknown. We report here that Med23 is required for adult hippocampal neurogenesis in mouse. Deletion of Med23 in adult hippocampal neural stem cells (NSCs) was achieved in Nestin-Cre^ER:Med23^flox/flox mice by oral administration of tamoxifen. We found an increased number of proliferating NSCs shown by pulse BrdU-labeling and immunostaining of MCM2 and Ki67, which is possibly due to a reduction in cell cycle length, with unchanged GFAP⁺/Sox2⁺ NSCs and Tbr2⁺ progenitors. On the other hand, neuroblasts and immature neurons indicated by NeuroD and DCX were decreased in number in the dentate gyrus (DG) of Med23-deficient mice. In addition, these mice also displayed defective dendritic morphogenesis, as well as a deficiency in spatial and contextual fear memory. Gene ontology (GO) analysis of hippocampal NSCs revealed an enrichment in genes involved in cell proliferation, Pol II-associated transcription, Notch signaling pathway and apoptosis. These results demonstrate that Med23 plays roles in regulating adult brain neurogenesis and functions.

Keywords: Mediator complex 23; adult neural stem cells; cell cycle; hippocampus; proliferation.