title: Murine Inhibin α-Subunit Haploinsufficiency Causes Transient Abnormalities in Prepubertal Testis Development Followed by Adult Testicular Decline.
abstract: Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-α gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-α concentrations in adult Inha+/- mice were approximately 33% lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11% larger than wild type and supported 44% greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27% reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-α subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.
authors.affiliation: Priority Research Centres for Reproductive Science (C.I., A.B., J.M., S.E.) and Chemical Biology (C.I.), School of Environmental and Life Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, New South Wales 2308, Australia; Departments of Anatomy and Developmental Biology (H.G., Q.L., K.L.L.) and Biochemistry and Molecular Biology (S.C.M., K.L.L.) and Monash Micro Imaging (A.J.F.), Monash University, Clayton, Victoria 3800, Australia; and Faculty of Medicine, Nursing, and Health Sciences (J.C.G.D.), Department of Medicine, Monash Medical Centre, and Monash Institute of Medical Research-Prince Henry's Institute of Medical Research (M.P.H.), Clayton, Victoria 3168, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Itman
authors.forename: Amanda
authors.initials: A
authors.lastname: Bielanowicz
authors.forename: Hoey
authors.initials: H
authors.lastname: Goh
authors.forename: Queenie
authors.initials: Q
authors.lastname: Lee
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Fulcher
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Moody
authors.forename: James C G
authors.initials: JC
authors.lastname: Doery
authors.forename: Jacinta
authors.initials: J
authors.lastname: Martin
authors.forename: Sarah
authors.initials: S
authors.lastname: Eyre
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hedger
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D005434:Flow Cytometry; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics / Q000502:physiology*; D007265:Inhibins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011627:Puberty / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D013094:Spermatozoa / Q000378:metabolism / Q000502:physiology; D013737:Testis / Q000378:metabolism* / Q000502:physiology*
chemical_list: C094377:inhibin-alpha subunit; D028341:Activins; D007265:Inhibins; D005640:Follicle Stimulating Hormone