title: Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling.
abstract: Ppard(-/-) mice exhibit smaller litter size compared with Ppard(+/+) mice. To determine whether peroxisome proliferator-activated receptor-D (PPARD) could possibly influence this phenotype, the role of PPARD in testicular biology was examined. Atrophic testes and testicular degeneration were observed in Ppard(-/-) mice compared with Ppard(+/+) mice, indicating that PPARD modulates spermatogenesis. Higher expression of p27 and decreased expression of proliferating cellular nuclear antigen in Sertoli cells were observed in Ppard(+/+) mice as compared with Ppard(-/-) mice, and these were associated with decreased Sertoli cell number in Ppard(+/+) mice. Cyclin D1 and cyclin D2 expression was lower in Ppard(+/+) as compared with Ppard(-/-) mice. Ligand activation of PPARD inhibited proliferation of a mouse Sertoli cell line, TM4, and an inverse agonist of PPARD (DG172) rescued this effect. Temporal inhibition of extracellular signal-regulated kinase (ERK) activation by PPARD in the testis was observed in Ppard(+/+) mice and was associated with decreased serum follicle-stimulating hormone and higher claudin-11 expression along the blood-testis barrier. PPARD-dependent ERK activation also altered expression of claudin-11, p27, cyclin D1, and cyclin D2 in TM4 cells, causing inhibition of cell proliferation, maturation, and formation of tight junctions in Sertoli cells, thus confirming a requirement for PPARD in accurate Sertoli cell function. Combined, these results reveal for the first time that PPARD regulates spermatogenesis by modulating the function of Sertoli cells during early testis development.
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, pxy11@psu.edu.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Yao
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: LiPing
authors.initials: L
authors.lastname: Chen
authors.affiliation: Reproductive Biology and Toxicology, Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 61802.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Hess
authors.affiliation: Institute of Molecular Biology and Tumor Research, Center for Tumor and Immunobiology, Philipps University, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany, and.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, jmp21@psu.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D057167:Claudins / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D056742:Cyclin D2 / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D013091:Spermatogenesis / Q000502:physiology*
chemical_list: C530105:Ccnd1 protein, mouse; C486196:Ccnd2 protein, mouse; D057167:Claudins; C492354:Cldn11 protein, mouse; D056742:Cyclin D2; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Sertoli cells; cell proliferation; extracellular signal-regulated kinase; peroxisome proliferator-activated receptor (PPAR); spermatogenesis; testis; tight junction