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Published on: February 6, 2018
Impaired fertility in mice deficient for the testicular germ-cell protease PC4
1Laboratory of Molecular, Clinical Research Institute of Montreal, University of Montreal, Montreal QC, Canada H2W 1R7. mbikaym@ircm.umontreal.ca
Abstract:
PC4 is a member of the proprotein convertase family of serine proteases implicated in the processing of a variety of polypeptides including prohormones, proneuropeptides, and cell surface proteins. In rodents, PC4 transcripts have been detected in spermatocytes and round spermatids exclusively, suggesting a reproductive function for this enzyme. In an effort to elucidate this function, we have disrupted its locus (Pcsk4) by homologous recombination in embryonic stem cells and have produced mice carrying the mutation. In intercrosses of heterozygous mutant mice, there was low transmission of the mutant Pcsk4 allele to the progeny, resulting in lower than expected incidence of heterozygosity and null homozygosity. The in vivo fertility of homozygous mutant males was severely impaired in the absence of any evident spermatogenic abnormality. In vitro, the fertilizing ability of Pcsk4 null spermatozoa was also found to be significantly reduced. Moreover, eggs fertilized by these spermatozoa failed to grow to the blastocyst stage. These results suggest that PC4 in the male may be important for achieving fertilization and for supporting early embryonic development in mice.
Insights
Proprotein convertase 4 (PC4) is crucial for male fertility and early embryonic development in mice. Its absence impairs sperm function and fertilization, leading to developmental failure post-fertilization.
Area of Science:
- Reproductive biology
- Molecular genetics
- Enzymology
Background:
- Proprotein convertase 4 (PC4) is a serine protease involved in polypeptide processing.
- PC4 transcripts are exclusively found in rodent male germ cells, suggesting a reproductive role.
- The specific function of PC4 in male reproduction remains largely unelucidated.
Purpose of the Study:
- To investigate the reproductive function of PC4 by creating and analyzing Pcsk4-deficient mice.
- To determine the impact of PC4 deficiency on male fertility and early embryonic development.
Main Methods:
- Gene disruption of the Pcsk4 locus in mouse embryonic stem cells using homologous recombination.
- Generation of Pcsk4 mutant mice and analysis of allele transmission.
- Assessment of in vivo fertility in homozygous mutant males.
- In vitro fertilization assays using spermatozoa from Pcsk4 null mice.
- Evaluation of early embryonic development after fertilization with mutant spermatozoa.
Main Results:
- Homozygous Pcsk4 mutant males exhibited severely impaired in vivo fertility.
- No apparent abnormalities in spermatogenesis were observed in mutant males.
- In vitro fertilization assays showed significantly reduced fertilizing ability of Pcsk4 null spermatozoa.
- Embryos fertilized by Pcsk4 null spermatozoa failed to develop to the blastocyst stage.
Conclusions:
- PC4 plays a critical role in male fertility in mice.
- PC4 is essential for successful fertilization and subsequent early embryonic development.
- The findings highlight PC4 as a key factor in male reproductive success and embryogenesis.
