title: The Luteinizing Hormone-Testosterone Pathway Regulates Mouse Spermatogonial Stem Cell Self-Renewal by Suppressing WNT5A Expression in Sertoli Cells.
abstract: Spermatogenesis originates from self-renewal of spermatogonial stem cells (SSCs). Previous studies have reported conflicting roles of gonadotropic pituitary hormones in SSC self-renewal. Here, we explored the role of hormonal regulation of SSCs using Fshb and Lhcgr knockout (KO) mice. Although follicle-stimulating hormone (FSH) is thought to promote self-renewal by glial cell line-derived neurotrophic factor (GDNF), no abnormalities were found in SSCs and their microenvironment. In contrast, SSCs were enriched in Lhcgr-deficient mice. Moreover, wild-type SSCs transplanted into Lhcgr-deficient mice showed enhanced self-renewal. Microarray analysis revealed that Lhcgr-deficient testes have enhanced WNT5A expression in Sertoli cells, which showed an immature phenotype. Since WNT5A was upregulated by anti-androgen treatment, testosterone produced by luteinizing hormone (LH) is required for Sertoli cell maturation. WNT5A promoted SSC activity both in vitro and in vivo. Therefore, FSH is not responsible for GDNF regulation, while LH negatively regulates SSC self-renewal by suppressing WNT5A via testosterone.
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Takashi
authors: T
authors: Tanaka
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Japan Science and Technology Agency, PRESTO, Kyoto 606-8501, Japan.
authors: Mito
authors: M
authors: Kanatsu-Shinohara
authors: Department of OB/GYN and Women's Health, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Zhenmin
authors: Z
authors: Lei
authors: Departments of Cellular Biology and Pharmacology, Molecular and Human Genetics, and Obstetrics and Gynecology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
authors: C V
authors: CV
authors: Rao
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address: tshinoha@virus.kyoto-u.ac.jp.
authors: Takashi
authors: T
authors: Shinohara
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal; D060833:Cellular Microenvironment; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D011974:Receptors, LH / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D013093:Spermatogonia / Q000166:cytology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D000071818:Wnt-5a Protein / Q000378:metabolism*
chemical_list: D011974:Receptors, LH; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone