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The protein phosphatase isoform PP1?1 substitutes for PP1?2 to support spermatogenesis but not normal sperm function and fertility†.

ABSTRACT: Four isoforms of serine/threonine phosphatase type I, PP1?, PP1?, PP1?1, and PP1?2, are derived from three genes. The PP1?1 and PP1?2 isoforms are alternately spliced transcripts of the protein phosphatase 1 catalytic subunit gamma gene (Ppp1cc). While PP1?1 is ubiquitous in somatic cells, PP1?2 is expressed exclusively in testicular germ cells and sperm. Ppp1cc knockout male mice (-/-), lacking both PP1?1 and PP1?2, are sterile due to impaired sperm morphogenesis. Fertility and normal sperm function can be restored by transgenic expression of PP1?2 alone in testis of Ppp1cc (-/-) mice. The purpose of this study was to determine whether the PP1?1 isoform is functionally equivalent to PP1?2 in supporting spermatogenesis and male fertility. Significant levels of transgenic PP1?1 expression occurred only when the transgene lacked a 1-kb 3?UTR region immediately following the stop codon of the PP1?1 transcript. PP1?1 was also incorporated into sperm at levels comparable to PP1?2 in sperm from wild-type mice. Spermatogenesis was restored in mice expressing PP1?1 in the absence of PP1?2. However, males from the transgenic rescue lines were subfertile. Sperm from the PP1?1 rescue mice were unable to fertilize eggs in vitro. Intrasperm localization of PP1?1 and the association of the protein regulators of the phosphatase were altered in epididymal sperm in transgenic PP1?1 compared to PP1?2. Thus, the ubiquitous isoform PP1?1, not normally expressed in differentiating germ cells, could replace PP1?2 to support spermatogenesis and spermiation. However, PP1?2, which is the PP1 isoform in mammalian sperm, has an isoform-specific role in supporting normal sperm function and fertility.

SUBMITTER: Dudiki T

PROVIDER: S-EPMC6437266 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The protein phosphatase isoform PP1γ1 substitutes for PP1γ2 to support spermatogenesis but not normal sperm function and fertility†.

Dudiki Tejasvi T Joudeh Nidaa N Sinha Nilam N Goswami Suranjana S Eisa Alaa A Kline Douglas D Vijayaraghavan Srinivasan S

Biology of reproduction 20190301 3

Four isoforms of serine/threonine phosphatase type I, PP1α, PP1β, PP1γ1, and PP1γ2, are derived from three genes. The PP1γ1 and PP1γ2 isoforms are alternately spliced transcripts of the protein phosphatase 1 catalytic subunit gamma gene (Ppp1cc). While PP1γ1 is ubiquitous in somatic cells, PP1γ2 is expressed exclusively in testicular germ cells and sperm. Ppp1cc knockout male mice (-/-), lacking both PP1γ1 and PP1γ2, are sterile due to impaired sperm morphogenesis. Fertility and normal sperm fun ...[more]

PMID: 30379985

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Project description:Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the removal of excess cytoplasm; therefore, we hypothesized that macroautophagy/autophagy might be involved in the process. To test this hypothesis, we examined the function of ATG5, a core autophagy protein in male germ cell development. Floxed Atg5 and Stra8- iCre mice were crossed to conditionally inactivate Atg5 in male germ cells. In Atg5flox/flox; Stra8- iCre mutant mice, testicular expression of the autophagosome marker LC3A/B-II was significantly reduced, and expression of autophagy receptor SQSTM1/p62 was significantly increased, indicating a decrease in testicular autophagy activity. The fertility of mutant mice was dramatically reduced with about 70% being infertile. Sperm counts and motility were also significantly reduced compared to controls. Histological examination of the mutant testes revealed numerous, large residual bodies in the lumen of stages after their normal resorption within the seminiferous epithelium. The cauda epididymal lumen was filled with sloughed germ cells, large cytoplasmic bodies, and spermatozoa with disorganized heads and tails. Examination of cauda epididymal sperm by electron microscopy revealed misshapen sperm heads, a discontinuous accessory structure in the mid-piece and abnormal acrosome formation and loss of sperm individualization. Immunofluorescence staining of epididymal sperm showed abnormal mitochondria and acrosome distribution in the mutant mice. ATG5 was shown to induce autophagy by mediating multiple signals to maintain normal developmental processes. Our study demonstrated ATG5 is essential for male fertility and is involved in various aspects of spermiogenesis.Abbreviations: AKAP4: a-kinase anchoring protein 4; ATG5: autophagy-related 5; ATG7: autophagy-related 7; ATG10: autophagy-related 10; ATG12: autophagy-related 12; cKO: conditional knockout; DDX4: DEAD-box helicase 4; MAP1LC3/LC3/tg8: microtubule-associated protein 1 light chain 3; PBS: phosphate-buffered saline; PIWIL2/MILI: piwi like RNA-mediated gene silencing 2; RT-PCR: reverse transcription-polymerase chain reaction; SQSTM1/p62: sequestosome 1; TBC: tubulobulbar complexes; WT: wild type.

Dataset Information

The protein phosphatase isoform PP1?1 substitutes for PP1?2 to support spermatogenesis but not normal sperm function and fertility†.

Publications

The protein phosphatase isoform PP1γ1 substitutes for PP1γ2 to support spermatogenesis but not normal sperm function and fertility†.

Similar Datasets

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