Interaction between DMRT1 and PLZF protein regulates self-renewal and proliferation in male germline stem cells

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Interaction between DMRT1 and PLZF protein regulates self‑renewal and proliferation in male germline stem cells Yudong Wei1 · Donghui Yang1 · Xiaomin Du1 · Xiuwei Yu1 · Mengfei Zhang1 · Furong Tang1 · Fanglin Ma1 · Na Li1 · Chunling Bai2 · Guangpeng Li2 · Jinlian Hua1  Received: 15 June 2020 / Accepted: 6 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Double sex and mab-3 related transcription factor 1 (DMRT1) encodes a double sex/mab-3 (DM) domain, which is the most conserved structure that involved in sex determination both in vertebrates and invertebrates. This study revealed important roles of DMRT1 in maintaining self-renewal of male germline stem cells (mGSCs). Our results showed that insufficient expression of DMRT1 in mice testes resulted in decreased number of spermatogonial cells and collapse of testicular niche in vivo. Self-renewal and proliferation of mGSCs were inhibited. Based on the bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (co-IP) assay, it was finally revealed that the interaction between DMRT1 and promyelocytic leukemia zinc finger (PLZF) protein was essential for maintaining self-renewal of mGSCs. Moreover, BTB domain of PLZF, DM and DMRT1 domain of DMRT1 were indispensable in mGSC, which were responsible for preserving the quantity of germ cells. Our research provided a new scientific basis for studying the mechanism of self-renewal and spermatogenesis in goat mGSCs. Keywords  DMRT1 · PLZF · Male germline stem cells (mGSCs) · Proliferation · Self-renewal

Introduction Doublesex- and mab-3-related transcription factor 1 (DMRT1) belongs to the DM domain gene family, which encodes transcription factors contain a DNA-binding region called DM domain. DMRT1 is important in testis formation and gonadal somatic-cell masculinization [1]. Studies have shown that DMRT1 is essential for maintaining self-renewal Yudong Wei and Donghui Yang contributed equally to this manuscript. Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1101​0-020-03977​-3) contains supplementary material, which is available to authorized users. * Jinlian Hua [email protected] 1



College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, No. 3rd, Taicheng Road, Yangling 712100, Shaanxi, China



Key Laboratory for Mammalian Reproductive Biology and Biotechnology, Ministry of Education, Inner Mongolia University, Hohhot 010021, China

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of mGSCs. Knockout of DMRT1 resulted in the gradual loss of germ cells, which in turn led to deletion of ID4 (inhibitor DNA binding 4) and GFRα1 (glial cell line derived neurotrophic factorα1) double positive mGSCs [2]. Busulfan is widely used as an alkylating agent in anti-leukemia drugs, however, busulfan also causes serious negative effects, for example, causing reproductive damages. Our previous research showed that DMRT1 promotes the proliferation of mGSCs in busulfan-treated mouse testis [2]. Thus, DMRT1 pl