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.
Highlights
The role of peroxisome proliferator-activated receptor-D (PPARD) was examined in the testes because this receptor can regulate cell differentiation and proliferation
Atrophic testes were only observed in PpardϪ/Ϫ mice from PND21 through PND56, and the average atrophic testis weight was gradually increased over time (Fig. 1G)
The average non-atrophic testis weight/litter in PpardϪ/Ϫ mice was larger than in Ppardϩ/ϩ mice over time (Fig. 1H). This contributed to the increase in average non-atrophic testis/body weight ratio in PpardϪ/Ϫ mice compared with Ppardϩ/ϩ mice (Fig. 1I)
Summary
The role of PPARD was examined in the testes because this receptor can regulate cell differentiation and proliferation. Atrophic testes and testicular degeneration were observed in Ppard؊/؊ mice compared with Ppard؉/؉ mice, indicating that PPARD modulates spermatogenesis. 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 altered expression of claudin-11, p27, cyclin D1, and cyclin D2 in TM4 cells, causing inhibition of cell proliferation, maturation, and formation of. 23416 JOURNAL OF BIOLOGICAL CHEMISTRY tight junctions in Sertoli cells, 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. The hypothesis that PPARD modulates testis development by directly influencing germ cell maturation or indirectly affecting the function of Sertoli cells and Leydig cells, limiting their supportive capacity to germ cell development, was examined in the present study
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