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Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis

View Article: PubMed Central - PubMed

ABSTRACT

The PRL phosphatases are oncogenic when overexpressed but their in vivo biological function is less well understood. Previous gene deletion study revealed a role for PRL2 in spermatogenesis. We report here the first knockout mice lacking PRL1, the most related homolog of PRL2. We found that loss of PRL1 does not affect spermatogenesis and reproductive ability of male mice, likely due to functional compensation by the relatively higher expression of PRL2 in the testes. However, PRL1−/−/PRL2+/− male mice show testicular atrophy phenotype similar to PRL2−/− mice. More strikingly, deletion of one PRL1 allele in PRL2−/− male mice causes complete infertility. Mechanistically, the total level of PRL1 and PRL2 is negatively correlated with the PTEN protein level in the testis and PRL1+/−/PRL2−/− mice have the highest level of PTEN, leading to attenuated Akt activation and increased germ cell apoptosis, effectively halting spermatozoa production. These results provide the first evidence that in addition to PRL2, PRL1 is also required for spermatogenesis by downregulating PTEN and promoting Akt signaling. The ability of the PRLs to suppress PTEN expression underscores the biochemical basis for their oncogenic potential.

No MeSH data available.


Related in: MedlinePlus

PRL1 is also required to prevent germ cells from apoptosis.(A) Testis sections from 3 month old male mice were histologically examined by immunohistochemical staining for Cleaved PARP and PCNA. (B,C) Number of cleaved-PARP positive cell per field (B) and percentage of PCNA positive cells per tubule (C) in testis sections from five genotypes were determined. For each mouse, at least 10 fields or 20 tubules were counted. **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.
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f5: PRL1 is also required to prevent germ cells from apoptosis.(A) Testis sections from 3 month old male mice were histologically examined by immunohistochemical staining for Cleaved PARP and PCNA. (B,C) Number of cleaved-PARP positive cell per field (B) and percentage of PCNA positive cells per tubule (C) in testis sections from five genotypes were determined. For each mouse, at least 10 fields or 20 tubules were counted. **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.

Mentions: Spermatogenesis is a precisely controlled process including germ cell proliferation, differentiation, self-renewal and apoptosis. Germ cell loss occurs normally during spermatogenesis in all mammals, and control of germ cell apoptosis during spermatogenesis is especially important. To determine whether loss of Kit-positive germ cells was due to decreased proliferation or increased apoptosis, we performed immunohistochemistry with PCNA (Proliferating Cell Nuclear Antigen, a proliferation marker) staining and cleaved PARP (Poly ADP-Ribose Polymerase, an apoptosis marker) staining to label proliferating and apoptotic cells respectively. As shown in Fig. 5A,C, the percentage of proliferating cells in the testis was similar in all five genotypes. In contrast, the number of cleaved PARP positive cells was 3-fold higher in PRL2−/− compared to wild-type or PRL1−/− testis (Fig. 5A,B). PRL1−/−/PRL2+/− mice also showed a 1.6 fold higher apoptosis compared to the control groups (Fig. 5A,B). More importantly, deletion of one PRL1 allele in PRL2−/− mice led to an additional 3-fold increase in apoptosis in comparison to PRL2−/− alone (Fig. 5A,B). The aggravated phenotype of PRL1+/−/PRL2−/− mice compared to PRL2- mice further supports an important role of PRL1 in spermatogenesis by promoting Kit-positive germ cell survival.


Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis
PRL1 is also required to prevent germ cells from apoptosis.(A) Testis sections from 3 month old male mice were histologically examined by immunohistochemical staining for Cleaved PARP and PCNA. (B,C) Number of cleaved-PARP positive cell per field (B) and percentage of PCNA positive cells per tubule (C) in testis sections from five genotypes were determined. For each mouse, at least 10 fields or 20 tubules were counted. **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035919&req=5

f5: PRL1 is also required to prevent germ cells from apoptosis.(A) Testis sections from 3 month old male mice were histologically examined by immunohistochemical staining for Cleaved PARP and PCNA. (B,C) Number of cleaved-PARP positive cell per field (B) and percentage of PCNA positive cells per tubule (C) in testis sections from five genotypes were determined. For each mouse, at least 10 fields or 20 tubules were counted. **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.
Mentions: Spermatogenesis is a precisely controlled process including germ cell proliferation, differentiation, self-renewal and apoptosis. Germ cell loss occurs normally during spermatogenesis in all mammals, and control of germ cell apoptosis during spermatogenesis is especially important. To determine whether loss of Kit-positive germ cells was due to decreased proliferation or increased apoptosis, we performed immunohistochemistry with PCNA (Proliferating Cell Nuclear Antigen, a proliferation marker) staining and cleaved PARP (Poly ADP-Ribose Polymerase, an apoptosis marker) staining to label proliferating and apoptotic cells respectively. As shown in Fig. 5A,C, the percentage of proliferating cells in the testis was similar in all five genotypes. In contrast, the number of cleaved PARP positive cells was 3-fold higher in PRL2−/− compared to wild-type or PRL1−/− testis (Fig. 5A,B). PRL1−/−/PRL2+/− mice also showed a 1.6 fold higher apoptosis compared to the control groups (Fig. 5A,B). More importantly, deletion of one PRL1 allele in PRL2−/− mice led to an additional 3-fold increase in apoptosis in comparison to PRL2−/− alone (Fig. 5A,B). The aggravated phenotype of PRL1+/−/PRL2−/− mice compared to PRL2- mice further supports an important role of PRL1 in spermatogenesis by promoting Kit-positive germ cell survival.

View Article: PubMed Central - PubMed

ABSTRACT

The PRL phosphatases are oncogenic when overexpressed but their in vivo biological function is less well understood. Previous gene deletion study revealed a role for PRL2 in spermatogenesis. We report here the first knockout mice lacking PRL1, the most related homolog of PRL2. We found that loss of PRL1 does not affect spermatogenesis and reproductive ability of male mice, likely due to functional compensation by the relatively higher expression of PRL2 in the testes. However, PRL1&minus;/&minus;/PRL2+/&minus; male mice show testicular atrophy phenotype similar to PRL2&minus;/&minus; mice. More strikingly, deletion of one PRL1 allele in PRL2&minus;/&minus; male mice causes complete infertility. Mechanistically, the total level of PRL1 and PRL2 is negatively correlated with the PTEN protein level in the testis and PRL1+/&minus;/PRL2&minus;/&minus; mice have the highest level of PTEN, leading to attenuated Akt activation and increased germ cell apoptosis, effectively halting spermatozoa production. These results provide the first evidence that in addition to PRL2, PRL1 is also required for spermatogenesis by downregulating PTEN and promoting Akt signaling. The ability of the PRLs to suppress PTEN expression underscores the biochemical basis for their oncogenic potential.

No MeSH data available.


Related in: MedlinePlus