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Complementary critical functions of Zfy1 and Zfy2 in mouse spermatogenesis and reproduction.

ABSTRACT: The mammalian Y chromosome plays a critical role in spermatogenesis. However, the exact functions of each gene in the Y chromosome have not been completely elucidated, partly owing to difficulties in gene targeting analysis for the Y chromosome. Zfy was first proposed to be a sex determination factor, but its function in spermatogenesis has been recently elucidated. Nevertheless, Zfy gene targeting analysis has not been performed thus far. Here, we adopted the highly efficient CRISPR/Cas9 system to generate individual Zfy1 or Zfy2 knockout (KO) mice, and Zfy1 and Zfy2 double knockout (Zfy1/2-DKO) mice. While individual Zfy1 or Zfy2-KO mice did not show any significant phenotypic alterations in fertility, Zfy1/2-DKO mice were infertile and displayed abnormal sperm morphology, fertilization failure, and early embryonic development failure. Mass spectrometric screening, followed by confirmation with western blot analysis, showed that PLCZ1, PLCD4, PRSS21, and HTT protein expression was significantly deceased in spermatozoa from Zfy1/2-DKO mice compared with those from wild type mice. These results are consistent with the phenotypic changes seen in the double mutant mice. Collectively, our strategy and findings revealed that Zfy1 and Zfy2 have redundant functions in spermatogenesis, facilitating a better understanding of fertilization failure and early embryonic development failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE90103 | GEO | 2017/01/12

SECONDARY ACCESSION(S): PRJNA354420

REPOSITORIES: GEO

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Project description:The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Equal amounts of detergent soluble cortical bone protein were subject to Tandem Mass Tags (TMT) quantitative proteomics. 3,429 proteins met the selection criteria (FDR≤ 1% and 2 peptide spectral matches). 181 proteins were differentially abundant in both male and female DKO bones (≥1.95 fold or ≤0.55 fold compared to wild-type). Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included “ECM degradation” and “Quantity of Monocytes.” Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male DKO and WT mice. DKO mice were smaller than WT. DKO femora had reduced cross-sectional area with a flattened, less circular cross-section. DKO bones were less stiff in bending, but this reduction was disproportionate to the decreases in bending moment of inertia on nanoCT leading to a modest increase in predicted modulus (stiffness/bending moment). DKO displayed a lower ultimate load along with increases in both ultimate displacement and yield displacement. The ratio of ultimate displacement to yield displacement was actually higher in DKO, suggesting that decreased yield displacement does not account entirely for the reduction in ultimate displacement. Together, these mechanical attributes suggest compensation for small bone size through mechanisms that are not explained by nanoCT structural analysis. DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with increased osteoblast numbers and osteoid surface. Marrow-derived colony forming unit-fibroblastic was reduced in DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique bone phenotype not predicted by the single knockouts, is manifested

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Complementary critical functions of Zfy1 and Zfy2 in mouse spermatogenesis and reproduction.

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