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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.


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PRL1 also contributes to the normal testis development.(A) Representative testis picture from five different genotypes. (B,C) Testis weights (B) or testis weight/body weight ratios (C) from five different genotypes were determined. *p < 0.05, **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD).
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f2: PRL1 also contributes to the normal testis development.(A) Representative testis picture from five different genotypes. (B,C) Testis weights (B) or testis weight/body weight ratios (C) from five different genotypes were determined. *p < 0.05, **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD).

Mentions: One of the major phenotypes for PRL2−/− mice is testicular atrophy21. Interestingly, both PRL1 and PRL2, but not PRL3, are expressed in testis, and the relative PRL1/PRL2 protein level is significantly higher in testis than those from other organs (Figure S4A). This finding suggests that PRL1 and PRL2, but not PRL3, may play essential roles in testis function. To determine whether both PRL1 and PRL2 are required for spermatogenesis, we focused on the testis phenotype in PRL1−/−/PRL2+/− and PRL1+/−/PRL2−/− mice. Anatomical examination was performed on adult males of different genotypes. Similar to our previous study21, the testis of PRL2 mice is 43 ± 8% smaller than that of wild-type mice (Fig. 2A,B). Strikingly, deletion of a single allele of PRL1 gene from the PRL2- mice caused an additional 59 ± 16% reduction of testis size, indicating that PRL1 is indeed involved in testis development (Fig. 2A,B). This is further strengthened by the observation that the testes of PRL1−/−/PRL2+/− male mice were also markedly smaller than those of wild-type animals (33 ± 14% reduction) (Fig. 2A,B), despite the fact that testis development in either PRL1−/− or PRL2+/− mice is normal. Since the body weight of PRL1−/−/PRL2+/− and especially PRL1+/−/PRL2−/− male mice was also reduced (Fig. 1C), we normalized the testis weight to body weight and still found a significant reduction of the testis/body weight ratio in PRL1−/−/PRL2+/− and especially PRL1+/−/PRL2−/− mice. As shown in Fig. 2C, while the testis/body weight ratio observed in PRL2−/− males decreased 33 ± 16% compared to the wild-type animals, deletion of one more PRL1 allele resulted in a 69 ± 9% reduction in the normalized testis size. Moreover, although no significant difference was observed in PRL1−/− mice, the testis/body weight ratio of PRL1−/−/PRL2+/− testis reduced 19 ± 12% compared to the wild-type mice (Fig. 2C).


Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis
PRL1 also contributes to the normal testis development.(A) Representative testis picture from five different genotypes. (B,C) Testis weights (B) or testis weight/body weight ratios (C) from five different genotypes were determined. *p < 0.05, **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: PRL1 also contributes to the normal testis development.(A) Representative testis picture from five different genotypes. (B,C) Testis weights (B) or testis weight/body weight ratios (C) from five different genotypes were determined. *p < 0.05, **p < 0.01, ***p < 0.001 (Student’s t test). Data are representative of at least three independent experiments (mean and SD).
Mentions: One of the major phenotypes for PRL2−/− mice is testicular atrophy21. Interestingly, both PRL1 and PRL2, but not PRL3, are expressed in testis, and the relative PRL1/PRL2 protein level is significantly higher in testis than those from other organs (Figure S4A). This finding suggests that PRL1 and PRL2, but not PRL3, may play essential roles in testis function. To determine whether both PRL1 and PRL2 are required for spermatogenesis, we focused on the testis phenotype in PRL1−/−/PRL2+/− and PRL1+/−/PRL2−/− mice. Anatomical examination was performed on adult males of different genotypes. Similar to our previous study21, the testis of PRL2 mice is 43 ± 8% smaller than that of wild-type mice (Fig. 2A,B). Strikingly, deletion of a single allele of PRL1 gene from the PRL2- mice caused an additional 59 ± 16% reduction of testis size, indicating that PRL1 is indeed involved in testis development (Fig. 2A,B). This is further strengthened by the observation that the testes of PRL1−/−/PRL2+/− male mice were also markedly smaller than those of wild-type animals (33 ± 14% reduction) (Fig. 2A,B), despite the fact that testis development in either PRL1−/− or PRL2+/− mice is normal. Since the body weight of PRL1−/−/PRL2+/− and especially PRL1+/−/PRL2−/− male mice was also reduced (Fig. 1C), we normalized the testis weight to body weight and still found a significant reduction of the testis/body weight ratio in PRL1−/−/PRL2+/− and especially PRL1+/−/PRL2−/− mice. As shown in Fig. 2C, while the testis/body weight ratio observed in PRL2−/− males decreased 33 ± 16% compared to the wild-type animals, deletion of one more PRL1 allele resulted in a 69 ± 9% reduction in the normalized testis size. Moreover, although no significant difference was observed in PRL1−/− mice, the testis/body weight ratio of PRL1−/−/PRL2+/− testis reduced 19 ± 12% compared to the wild-type mice (Fig. 2C).

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