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

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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 plays a role in maintaining spermatogenesis.(A) Testis sections from 3 months or 2 weeks old male mice were histologically examined by H&E staining and immunohistochemical staining for Vimentin, PLZF and Kit. (B–E) Relative seminiferous tubule diameters (B), number of Vimentin positive cell per seminiferous tubule (C), number of c-Kit positive cell per tubule (D) and number of PLZF positive cell per tubule (E) in testis sections from all five genotypes were quantificated. For each mouse, at least 20 tubules were counted. *p < 0.05, **p < 0.01 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.
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f4: PRL1 also plays a role in maintaining spermatogenesis.(A) Testis sections from 3 months or 2 weeks old male mice were histologically examined by H&E staining and immunohistochemical staining for Vimentin, PLZF and Kit. (B–E) Relative seminiferous tubule diameters (B), number of Vimentin positive cell per seminiferous tubule (C), number of c-Kit positive cell per tubule (D) and number of PLZF positive cell per tubule (E) in testis sections from all five genotypes were quantificated. For each mouse, at least 20 tubules were counted. *p < 0.05, **p < 0.01 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.

Mentions: To further investigate how PRL1 is involved in controlling testis organ size and sperm production, the histological structures of 3-month-old male testis derived from different genotypes were analyzed by H&E staining. Even though the overall structures of the seminiferous tubules of 3-month-old male mice were similar between the different genotypes, the diameters of the seminiferous tubules were altered (Fig. 4A,B). Consistent with our previous study21, the diameter of the seminiferous tubules from the PRL2−/− testis decreased 21 ± 6% in comparison to those from the wild-type and PRL1−/− mice. There was also a 17 ± 3% and 27 ± 5% reduction in the diameter of the seminiferous tubules of the PRL1−/−/PRL2+/− and PRL1+/−/PRL2−/− testis, respectively (Fig. 4B). Moreover, loss of certain cell types was evidenced by the “empty space” observed inside of the seminiferous tubules of PRL2−/− testis, and this was even more severe in the PRL1+/−/PRL2−/− testis (Black arrows in Fig. 4A). In line with this observation, numerous round-shaped cells were released into the caudal epididymis of PRL2−/− mice, and even more round-shaped cells were observed in the caudal epididymis of PRL1+/−/PRL2−/− mice (Fig. 3E). In addition, re-expressing PRL2 in the testis successfully rescued the histological abnormality in PRL1+/−/PRL2−/− testis (Figure S5F, top panel). These data indicated that the combined level of PRL1 and PRL2 is important for maintaining spermatogenesis and that the reduced testis size is mainly attributed to decreased cellularity in the seminiferous tubules.


Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis
PRL1 also plays a role in maintaining spermatogenesis.(A) Testis sections from 3 months or 2 weeks old male mice were histologically examined by H&E staining and immunohistochemical staining for Vimentin, PLZF and Kit. (B–E) Relative seminiferous tubule diameters (B), number of Vimentin positive cell per seminiferous tubule (C), number of c-Kit positive cell per tubule (D) and number of PLZF positive cell per tubule (E) in testis sections from all five genotypes were quantificated. For each mouse, at least 20 tubules were counted. *p < 0.05, **p < 0.01 (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

f4: PRL1 also plays a role in maintaining spermatogenesis.(A) Testis sections from 3 months or 2 weeks old male mice were histologically examined by H&E staining and immunohistochemical staining for Vimentin, PLZF and Kit. (B–E) Relative seminiferous tubule diameters (B), number of Vimentin positive cell per seminiferous tubule (C), number of c-Kit positive cell per tubule (D) and number of PLZF positive cell per tubule (E) in testis sections from all five genotypes were quantificated. For each mouse, at least 20 tubules were counted. *p < 0.05, **p < 0.01 (Student’s t test). Data are representative of at least three independent experiments (mean and SD). Scale bar = 50 μm.
Mentions: To further investigate how PRL1 is involved in controlling testis organ size and sperm production, the histological structures of 3-month-old male testis derived from different genotypes were analyzed by H&E staining. Even though the overall structures of the seminiferous tubules of 3-month-old male mice were similar between the different genotypes, the diameters of the seminiferous tubules were altered (Fig. 4A,B). Consistent with our previous study21, the diameter of the seminiferous tubules from the PRL2−/− testis decreased 21 ± 6% in comparison to those from the wild-type and PRL1−/− mice. There was also a 17 ± 3% and 27 ± 5% reduction in the diameter of the seminiferous tubules of the PRL1−/−/PRL2+/− and PRL1+/−/PRL2−/− testis, respectively (Fig. 4B). Moreover, loss of certain cell types was evidenced by the “empty space” observed inside of the seminiferous tubules of PRL2−/− testis, and this was even more severe in the PRL1+/−/PRL2−/− testis (Black arrows in Fig. 4A). In line with this observation, numerous round-shaped cells were released into the caudal epididymis of PRL2−/− mice, and even more round-shaped cells were observed in the caudal epididymis of PRL1+/−/PRL2−/− mice (Fig. 3E). In addition, re-expressing PRL2 in the testis successfully rescued the histological abnormality in PRL1+/−/PRL2−/− testis (Figure S5F, top panel). These data indicated that the combined level of PRL1 and PRL2 is important for maintaining spermatogenesis and that the reduced testis size is mainly attributed to decreased cellularity in the seminiferous tubules.

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