Impaired fertility in mice deficient for the testicular germ-cell protease PC4

Impaired fertility in mice deficient for the testicular germ-cell protease PC4

Laboratories of ^*Molecular and ^‖Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal QC, Canada H2W 1R7; ^‡Urology Research Laboratory, Royal Victoria Hospital, McGill University, Montreal QC, Canada H3A 1A1; ^§The Jackson Laboratory, Bar Harbor, ME 04069; and ^¶Department of Anatomy, McGill University, Montreal, QC, Canada H3A 2B2

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.

Footnotes

↵ † To whom reprint requests should be addressed at: Laboratoire de Neuroendocrinologie Moléculaire, Institut de Recherches Cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal QC, Canada H2W 1R7. e-mail: mbikaym{at}ircm.umontreal.ca.
Melvin M. Grumbach, University of California School of Medicine, San Francisco, CA
ABBREVIATIONS:

ES,

embryonic stem;

β-gal,

β-galactosidase;

IVF,

in vitro fertilization;

neoR,

neomycin phosphotransferase gene;

PGK,

phosphoglycerate kinase;

tk,

thymidine kinase gene;

PCs,

proprotein convertases;

ALH,

amplitude of lateral head displacement