Spermatogonial Depletion in Adult Pin1-Deficient Mice1

Abstract

Spermatogonia in the mouse testis arise from early postnatal gonocytes that are derived from primordial germ cells (PGCs) during embryonic development. The proliferation, self-renewal, and differentiation of spermatogonial stem cells provide the basis for the continuing integrity of spermatogenesis. We previously reported that Pin1-deficient embryos had a profoundly reduced number of PGCs and that Pin1 was critical to ensure appropriate proliferation of PGCs. The current investigation aimed to elucidate the function of Pin1 in postnatal germ cell development by analyzing spermatogenesis in adult Pin1-/- mice. Although Pin1 was ubiquitously expressed in the adult testis, we found it to be most highly expressed in spermatogonia and Sertoli cells. Correspondingly, we show here that Pin1 plays an essential role in maintaining spermatogonia in the adult testis. Germ cells in postnatal Pin1-/- testis were able to initiate and complete spermatogenesis, culminated by production of mature spermatozoa. However, there was a progressive and age-dependent degeneration of the spermatogenic cells in Pin1-/- testis that led to complete germ cell loss by 14 mo of age. This depletion of germ cells was not due to increased cell apoptosis. Rather, detailed analysis of the seminiferous tubules using a germ cell-specific marker revealed that depletion of spermatogonia was the first step in the degenerative process and led to disruption of spermatogenesis, which resulted in eventual tubule degeneration. These results reveal that the presence of Pin1 is required to regulate proliferation and/or cell fate of undifferentiated spermatogonia in the adult mouse testis.

Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal

“…4D). Although Fbxw7 deficiency increased the concentration of SSCs, this result appeared to contradict a previous observation that Pin1 deficiency induced spermatogonia depletion (17), given that Pin1 depletion caused a decrease in FBXW7 level. Because PIN1 is also expressed in Sertoli cells and may influence spermatogenesis, we directly examined the impact of Pin1 depletion in germ cells by spermatogonial transplantation.…”

“…Fbxw7 is a tumor suppressor, and its expression needs to be tightly controlled in nontransformed cells. Indeed, PIN1 expression is inversely correlated with FBXW7 expression (14) whereas PIN1 expression was enhanced in undifferentiated relative to differentiating spermatogonia (17), suggesting another sophisticated regulation system. Because Pin1 depletion compromised SSC activity, we speculate that the balance between PIN1 and FBXW7 is critical in determining SSC fate and that disruption of this regulation may induce tumor formation.…”

PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans

“…Although expression of antisense Pin1 RNA in HeLa cells has been reported to induce a cell cycle arrest with a high percentage of cells containing condensed chromatin (14), the characterization of Pin1 null mice and fibroblasts has produced evidence for a critical role of Pin1 for G 1 progression. Pin1 null primordial germ cells and MEFs grow at a slower rate compared with controls, and MEFs are impaired in cell cycle re-entry following serum deprivation (9,11,12,18). At the biochemical level, Pin1 has been suggested to positively regulate numerous proteins important for or implicated in G 1 progression, including cyclinD1, c-Jun, and ␤-catenin (10,19,20).…”

Peptidyl-Prolyl Isomerase 1 (Pin1) Serves as a Coactivator of Steroid Receptor by Regulating the Activity of Phosphorylated Steroid Receptor Coactivator 3 (SRC-3/AIB1)

“…As Pin1 is important for the function of reproductive tissues in mice (4,5,23), we reasoned that Pin1 could play a role in the function of sex steroid receptors such as estrogen receptor (ER) and progesterone receptor (PR) by influencing the activities of one or more of their coactivators. Our attention was directed first to SRC-3/AIB1 because it is a dominant coactivator of PR and ER in certain reproductive tissues (19,42,52).…”