title: The mammalian Doublesex homolog DMRT6 coordinates the transition between mitotic and meiotic developmental programs during spermatogenesis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Teng
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Murphy
authors.affiliation: Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Micah D
authors.initials: MD
authors.lastname: Gearhart
authors.affiliation: Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
authors.affiliation: Developmental Biology Center, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA zarko001@umn.edu.
authors.forename: David
authors.initials: D
authors.lastname: Zarkower
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D055412:Growth Differentiation Factors / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008297:Male; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D017423:Sequence Analysis, RNA; D013091:Spermatogenesis / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001973:Bromodeoxyuridine; D017931:DNA Primers; D055412:Growth Differentiation Factors; D014157:Transcription Factors; C000593001:Dmrtb1 protein, Mouse
keywords: DMRT1; DMRT6; Meiosis; Mouse; Spermatogenesis; Testis