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The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

ABSTRACT: In the main olfactory epithelium (MOE), new olfactory sensory neurons (OSNs) are persistently generated to replace lost neurons throughout an organism's lifespan. This process predominantly depends on the proliferation of globose basal cells (GBCs), the actively dividing stem cells in the MOE. Here, by using CRISPR/Cas9 and RNAi coupled with adeno-associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR-200b/a in the MOE resulted in supernumerary Mash1-marked GBCs and decreased numbers of differentiated OSNs, accompanied by abrogation of male behaviors. We further showed that in the MOE, miR-200b/a targets the ten-eleven translocation methylcytosine dioxygenase TET3, which cooperates with RE1-silencing transcription factor (REST) to exert their functions. Deficiencies including proliferation, differentiation, and behaviors illustrated in miR-200b/a knockdown mice were rescued by suppressing either TET3 or REST. Our work describes a mechanism of coordination of GBC proliferation and differentiation in the MOE and olfactory male behaviors through miR-200/TET3/REST signaling.

SUBMITTER: Yang D

PROVIDER: S-EPMC7507367 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

Yang Dong D Wu Xiangbo X Zhou Yanfen Y Wang Weina W Wang Zhenshan Z

EMBO reports 20200717 9

In the main olfactory epithelium (MOE), new olfactory sensory neurons (OSNs) are persistently generated to replace lost neurons throughout an organism's lifespan. This process predominantly depends on the proliferation of globose basal cells (GBCs), the actively dividing stem cells in the MOE. Here, by using CRISPR/Cas9 and RNAi coupled with adeno-associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR-200b/a in the MOE resulted in supernumerary Mash1-marked GBCs a ...[more]

PMID: 32677323

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Project description:Ongoing, lifelong neurogenesis maintains the neuronal population of the olfactory epithelium in the face of piecemeal neuronal turnover and restores it following wholesale loss. The molecular phenotypes corresponding to different stages along the progression from multipotent globose basal cell (GBC) progenitor to differentiated olfactory sensory neuron are poorly characterized. We used the transgenic expression of GFP and cell surface markers to FACS-isolate Sox2-GFP(+) GBCs, Neurog1-GFP(+) GBCs and immature neurons, and OMP-GFP(+) mature neurons from normal adult mice. In addition, the latter two populations were also collected 3 weeks after olfactory bulb ablation, a lesion that results in persistently elevated neurogenesis. Global profiling of mRNA from the populations indicates that all stages of neurogenesis share a cohort of >2100 genes that are upregulated compared to sustentacular cells. A further cohort of >1200 genes are specifically upregulated in GBCs as compared to sustentacular cells and differentiated neurons. The increased rate of neurogenesis caused by olfactory bulbectomy had little effect on the transcriptional profile of the Neurog1-GFP(+) population. In contrast, the abbreviated lifespan of OMP-GFP(+) neurons born in the absence of the bulb correlated with substantial differences in gene expression as compared to the mature neurons of the normal epithelium. Detailed examination of the specific genes upregulated in the different progenitor populations revealed that the chromatin modifying complex proteins LSD1 and coREST were expressed sequentially in upstream Sox2-GFP(+) GBCs and Neurog1-GFP(+) GBCs/immature neurons. The expression patterns of these proteins are dynamically regulated after activation of the epithelium by methyl bromide lesion. Total RNA was isolated from dissected, dissociated and FACS-purified olfactory mucosal cells from normal adult mice or mice 3 weeks after unilateral bulbectomy. Cells were purified with FACS using endogenous GFP fluorescence from various transgenic lines and cell surface labeling. Two to seven adult mice were used per replicate and three replicates per condition were performed using Illumina bead arrays. 21 samples from olfactory mucosa were analyzed in this series and 3 samples were from a commercially available reference RNA sample. Universal mouse reference RNA from Stratagene was used as a general control and Normal olfactory mucosa was used as a tissue specific control.

Dataset Information

The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

Publications

The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

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