title: Androgen action via testicular peritubular myoid cells is essential for male fertility.
abstract: Androgens are essential for normal spermatogenesis and male fertility, but how androgens exert this effect remains uncertain. Androgen receptors (ARs) are expressed in several testicular cell types, but continuing uncertainty exists over which cell type mediates androgen control of spermatogenesis. Androgen signaling via Sertoli cells (SCs) is essential for complete spermatogenesis, but the role for androgen signaling via peritubular myoid (PTM) cells is contentious. To address this controversy, we generated PTM-specific AR-knockout (PTM-ARKO) mice in which gross reproductive development was normal, but all PTM-ARKO males were azoospermic and infertile. Testis weight was reduced beyond puberty, and in adulthood there was an 86% reduction in germ cells, compared with wild-type littermates. These changes were not explained by any deficits in testosterone, luteinizing hormone, or follicle-stimulating hormone concentrations. SC function was impaired in PTM-ARKO males, indicated by reduced seminiferous tubule fluid production and reduced expression of some androgen-dependent SC genes. Androgen action via PTM cells is therefore essential for normal testis function, spermatogenesis, and fertility in males. This study also provides the first direct evidence for the importance of androgen-driven stromal-epithelial interactions underpinning the regulation of spermatogenesis; PTM-ARKO mice will enable identification of the new molecular pathways involved.
authors.affiliation: MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Welsh
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.forename: Nina
authors.initials: N
authors.lastname: Atanassova
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D005260:Female; D005298:Fertility / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012671:Seminiferous Tubules / Q000166:cytology* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000728:Androgens; D011944:Receptors, Androgen
references.citation: J Cell Biol. 1985 Jun;100(6):1941-7
references.pmid: 3889013
references.citation: Anat Rec. 1994 Oct;240(2):225-32
references.pmid: 7992888
references.citation: J Mol Cell Cardiol. 2006 Oct;41(4):724-31
references.pmid: 16887142
references.citation: Proc Natl Acad Sci U S A. 1985 Jan;82(1):114-8
references.pmid: 3855533
references.citation: Endocrinology. 2006 Dec;147(12):5624-33
references.pmid: 16973730
references.citation: Endocr Rev. 1995 Jun;16(3):271-321
references.pmid: 7671849
references.citation: Endocrinology. 1994 Dec;135(6):2608-14
references.pmid: 7988449
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):7142-7
references.pmid: 11997476
references.citation: Hum Reprod. 2003 Jul;18(7):1383-94
references.pmid: 12832361
references.citation: J Androl. 2003 Mar-Apr;24(2):135-48
references.pmid: 12634296
references.citation: Int J Androl. 2008 Apr;31(2):74-80
references.pmid: 18194282
references.citation: Contraception. 2005 Oct;72(4):294-7
references.pmid: 16181974
references.citation: J Reprod Fertil. 1980 Jan;58(1):37-42
references.pmid: 6244406
references.citation: Andrologia. 2000 Jan;32(1):42-5
references.pmid: 10702865
references.citation: J Reprod Fertil. 1994 May;101(1):193-8
references.pmid: 8064681
references.citation: Endocrinology. 2004 Jan;145(1):318-29
references.pmid: 14551232
references.citation: J Androl. 2009 May-Jun;30(3):338-48
references.pmid: 19136388
references.citation: Cell. 1993 Aug 27;74(4):679-91
references.pmid: 8395349
references.citation: Recent Prog Horm Res. 2002;57:149-79
references.pmid: 12017541
references.citation: Physiol Genomics. 2002 Sep 03;10(3):211-5
references.pmid: 12209023
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1327-32
references.pmid: 14745012
references.citation: Reproduction. 2005 Oct;130(4):509-16
references.pmid: 16183868
references.citation: Endocrinology. 2005 Sep;146(9):4117-26
references.pmid: 15919750
references.citation: Int J Androl. 1983 Jun;6(3):249-60
references.pmid: 6411627
references.citation: Am J Anat. 1989 Mar;184(3):179-89
references.pmid: 2750675
references.citation: Biol Reprod. 2000 Nov;63(5):1403-12
references.pmid: 11058545
references.citation: Mol Endocrinol. 2006 Feb;20(2):321-34
references.pmid: 16166195
references.citation: Nature. 2001 Nov 1;414(6859):98-104
references.pmid: 11689954
references.citation: J Steroid Biochem. 1978 Apr;9(4):373-4
references.pmid: 96306
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6876-81
references.pmid: 15107499
references.citation: Endocrinology. 2006 Oct;147(10):4820-30
references.pmid: 16809447
references.citation: Endocrinology. 2005 Jun;146(6):2674-83
references.pmid: 15761038
references.citation: Endocrinology. 2003 Jan;144(1):138-45
references.pmid: 12488339
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17718-23
references.pmid: 17095600
references.citation: Transgenic Res. 2005 Oct;14(5):691-702
references.pmid: 16245160
references.citation: Biol Reprod. 1978 Feb;18(1):65-73
references.pmid: 626768
references.citation: Endocrinology. 2000 Nov;141(11):4284-94
references.pmid: 11089564
references.citation: Endocrinology. 2001 Jun;142(6):2405-8
references.pmid: 11356688
references.citation: Int Rev Cytol. 1976;47:137-94
references.pmid: 992959
references.citation: Reproduction. 2001 Aug;122(2):227-34
references.pmid: 11467973
references.citation: Endocrinology. 2009 May;150(5):2472-80
references.pmid: 19131576
references.citation: Biol Reprod. 1995 Feb;52(2):320-30
references.pmid: 7711202
references.citation: Arch Histol Cytol. 2004 Dec;67(5):417-34
references.pmid: 15781983