title: Neuregulin 1 Regulates Proliferation of Leydig Cells to Support Spermatogenesis and Sexual Behavior in Adult Mice.
abstract: Adult Leydig cells are derived from proliferating stem/progenitor Leydig cells in the infant testis and subsequent differentiation to steroidogenic cells in adult mice. Leydig cell proliferation in the infant testis occurs primarily in response to increased levels of LH that induce Leydig cell expression of neuregulin 1 (NRG1). Depletion of NRG1 in Nrg1 mutant mice (Nrg1flox;flox;Cyp19a1Cre mice) dramatically reduces Leydig cell proliferation in the infant testes, leading to a reduction of testis weight, epididymial weight, and serum T in the adult mutant mice. The mutant mice are subfertile due to impaired sexual behavior and abnormal elongation of the spermatogenic cells. These defects were reversed by T treatment of the mutant mice in vivo. Furthermore, NRG1 alone induces the proliferation of Leydig cells in cultures of infant (d 10) testes obtained from mutant mice. Collectively these results show that LH induction of NRG1 directly drives the proliferation of Leydig cells in the infant testis, leading to an obligatory number of adult Leydig cells required for the production of sufficient androgen to support and maintain spermatogenesis and sexual behavior of adult male mice.
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Ikko
authors.initials: I
authors.lastname: Kawashima
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hoshino
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Ken-Ichirou
authors.initials: KI
authors.lastname: Morohashi
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
authors.affiliation: Graduate School of Biosphere Science (T.U., I.K., T.K., Y.H., W.Z., M.S.), Hiroshima University, Higashi-Hiroshima 7398528, Japan; Laboratory of Sex Differentiation (K.M., Y.S.), Graduate School of Medicine, Kyusyu University, Fukuoka 8258585, Japan; College of Animal Science and Technology (W.Z., Y.S.), Northwest A&F University, Yangling, 712100 China; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D007985:Leydig Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology
chemical_list: D020890:Neuregulin-1; D013739:Testosterone