title: BMP4 promotes human Sertoli cell proliferation via Smad1/5 and ID2/3 pathway and its abnormality is associated with azoospermia.
abstract: Sertoli cell plays critical roles in regulating testis development and spermatogenesis. Any change in the number or biological functions of Sertoli cells can affect the normal formation of spermatozoa. However, the roles and molecular mechanisms of factors in controlling the fate determinations of human Sertoli cells and underlying male infertility remain unknown. Here we have for the first time explored the function and signaling pathway of BMP4 in regulating adult human Sertoli cells and their association with non-obstructive azoospermia (NOA) patients. Immunocytochemistry and immunohistochemistry revealed that BMP4 and its multiple receptors were present in human Sertoli cells. Cell proliferation and BrdU incorporation assays showed that BMP4 promoted DNA synthesis and proliferation of Sertoli cells. In contrast, BMP4 antagonist noggin and BMP4 knockdown reduced the division of Sertoli cells. Moreover, BMP4 knockdown inhibited the synthesis of FGF2, SCF, zonula occludens 1, and claudin 11 but enhanced p27kip1 transcription. BMP4 activated Smad1/5 phosphorylation and upregulated ID2 and ID3 transcription, whereas noggin counteracted these increases. Significantly, tissue arrays disclosed that overexpression of BMP4 may be associated with Sertoli cell-only syndrome and maturation arrest in spermatogonia or spermatocytes. BMP4 was identified as the first autocrine factor that regulates the proliferation and protein synthesis of human Sertoli cells via Smad1/5 and ID2/3 and its abnormality is associated with human non-obstructive azoospermia patients. This study thus provides novel insights into molecular mechanism underlying adult human Sertoli cell growth and offers new targets for gene therapy of male infertility.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Hai
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Andrology, Shanghai Human Sperm Bank, Shanghai 200001, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Andrology, Shanghai Human Sperm Bank, Shanghai 200001, China; Shanghai Key Laboratory of Assisted Reproduction and Reproductive Genetics, Shanghai 200127, China; and Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China.
authors.forename: Zuping
authors.initials: Z
authors.lastname: He
mesh_terms: D000328:Adult; D053713:Azoospermia / Q000378:metabolism*; D001706:Biopsy; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology*; D012844:Sincalide / Q000378:metabolism; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; C075640:ID3 protein, human; D012844:Sincalide