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-CreER:Med23flox/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.
Highlights
The mammalian Mediator complex is an evolutionarily conserved multi-protein complex, which functions as a key transcriptional cofactor by forming a link between sequence-specific transcription factors and the RNA polymerase II (Pol II)-associated basal transcription machinery
To visualize Mediator subunit 23 (Med23)-deficient neural stem cells (NSCs) and its progeny in vivo using Rosa26-stop-YFP mice (Romer et al, 2011), NestinCreER:Med23flox/flox:Rosa26-stop-YFP mice were generated by crossing NestinCreER:Rosa26-stop-YFP:Med23flox/+ mice with Med23flox/+ mice; in this set of experiments littermates with the genotype of Nestin-CreER:Rosa26-YFP:Med23+/+ were used as controls, because they did not show any detectable alterations in the subgranular zone (SGZ) either
To examine whether hippocampal NSCs are affected by the inactivation of Med23, we first performed bromo-2 -deoxyuridine (BrdU) pulse-labeling (Figure 1A) and quantified BrdU+ cells in the SGZ as reported in our previous study (Song et al, 2016)
Summary
The mammalian Mediator complex is an evolutionarily conserved multi-protein complex, which functions as a key transcriptional cofactor by forming a link between sequence-specific transcription factors and the RNA polymerase II (Pol II)-associated basal transcription machinery. In this context, it may be required for the transcription of thousands of protein-coding genes (Lewis and Reinberg, 2003; Malik and Roeder, 2005; Hentges, 2011). Based on data showing that mutation of different Mediator complex genes in the same organism leads to different phenotypes, individual Mediator complex proteins have unique biological functions (Bourbon et al, 2004; Malik and Roeder, 2010; Hentges, 2011). Important roles of Med have been reported in other biological processes including osteoblast differentiation (Liu et al, 2016), myogenesis (Yin et al, 2012), lung carcinogenesis (Yang et al, 2012; Yao et al, 2015), glucose and lipid metabolism (Chu et al, 2014), and T-cell activation (Sun et al, 2014)
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