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

Area of Science:

• Molecular Biology
• Reproductive Biology
• Oncology

Background:

• The PRL (Said) phosphatase family has oncogenic roles when overexpressed, but their in vivo functions, particularly PRL1, remain unclear.
• Previous studies indicated a role for PRL2 in spermatogenesis, but the specific function of its homolog, PRL1, in male reproduction is unknown.
• Understanding PRL phosphatases' biological roles is critical for their link to cancer and reproductive health.

Purpose of the Study:

• To investigate the in vivo biological function of PRL1, the closest homolog of PRL2, in male mice.
• To elucidate the roles of PRL1 and PRL2 in spermatogenesis and male reproductive capability.
• To determine the molecular mechanisms underlying PRL phosphatases' effects on PTEN/Akt signaling in the testis.

Main Methods:

• Generation and phenotypic analysis of PRL1 knockout mice.
• Generation and analysis of compound mutant mice (PRL1^-/-/PRL2^+/- and PRL2^-/-/PRL1^+/-).
• Assessment of spermatogenesis, testicular histology, PTEN protein levels, Akt activation, and germ cell apoptosis.

Main Results:

• PRL1 knockout alone did not affect male fertility, suggesting functional compensation by PRL2.
• Combined loss of one PRL1 allele and one PRL2 allele (PRL1^+/-/PRL2^-/-) resulted in complete male infertility and testicular atrophy.
• These infertile mice exhibited elevated PTEN levels, reduced Akt activation, and increased germ cell apoptosis, halting sperm production.

Conclusions:

• PRL1, in addition to PRL2, is essential for spermatogenesis in mice.
• PRL1 and PRL2 regulate spermatogenesis by downregulating PTEN protein levels and promoting Akt signaling.
• The ability of PRL phosphatases to suppress PTEN supports their oncogenic potential in other contexts.