Zhang Teng, Murphy Mark W, Gearhart Micah D, Bardwell Vivian J, Zarkower David
Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA Molecular, Cellular, Developmental Biology and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA.
Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Development. 2014 Oct;141(19):3662-71. doi: 10.1242/dev.113936.
In mammals, a key transition in spermatogenesis is the exit from spermatogonial differentiation and mitotic proliferation and the entry into spermatocyte differentiation and meiosis. Although several genes that regulate this transition have been identified, how it is controlled and coordinated remains poorly understood. Here, we examine the role in male gametogenesis of the Doublesex-related gene Dmrt6 (Dmrtb1) in mice and find that Dmrt6 plays a crucial role in directing germ cells through the mitotic-to-meiotic germ cell transition. DMRT6 protein is expressed in late mitotic spermatogonia. In mice of the C57BL/6J strain, a null mutation in Dmrt6 disrupts spermatogonial differentiation, causing inappropriate expression of spermatogonial differentiation factors, including SOHLH1, SOHLH2 and DMRT1 as well as the meiotic initiation factor STRA8, and causing most late spermatogonia to undergo apoptosis. In mice of the 129Sv background, most Dmrt6 mutant germ cells can complete spermatogonial differentiation and enter meiosis, but they show defects in meiotic chromosome pairing, establishment of the XY body and processing of recombination foci, and they mainly arrest in mid-pachynema. mRNA profiling of Dmrt6 mutant testes together with DMRT6 chromatin immunoprecipitation sequencing suggest that DMRT6 represses genes involved in spermatogonial differentiation and activates genes required for meiotic prophase. Our results indicate that Dmrt6 plays a key role in coordinating the transition in gametogenic programs from spermatogonial differentiation and mitosis to spermatocyte development and meiosis.
在哺乳动物中，精子发生过程中的一个关键转变是从精原细胞分化和有丝分裂增殖阶段退出，进入精母细胞分化和减数分裂阶段。尽管已经鉴定出了几个调节这一转变的基因，但对其如何被控制和协调仍知之甚少。在这里，我们研究了双性相关基因Dmrt6（Dmrtb1）在小鼠雄性配子发生中的作用，发现Dmrt6在引导生殖细胞从有丝分裂向减数分裂的生殖细胞转变过程中起着关键作用。DMRT6蛋白在有丝分裂后期的精原细胞中表达。在C57BL/6J品系的小鼠中，Dmrt6的无效突变破坏了精原细胞的分化，导致包括SOHLH1、SOHLH2和DMRT1在内的精原细胞分化因子以及减数分裂起始因子STRA8的不适当表达，并导致大多数晚期精原细胞发生凋亡。在129Sv背景的小鼠中，大多数Dmrt6突变的生殖细胞能够完成精原细胞分化并进入减数分裂，但它们在减数分裂染色体配对、XY体的形成和重组位点的处理方面存在缺陷，并且主要停滞在粗线期中期。对Dmrt6突变睾丸的mRNA谱分析以及DMRT6染色质免疫沉淀测序表明，DMRT6抑制参与精原细胞分化的基因，并激活减数分裂前期所需的基因。我们的结果表明，Dmrt6在协调配子发生程序从精原细胞分化和有丝分裂到精母细胞发育和减数分裂的转变中起关键作用。
