Clues To Impaired Male Infertility In Knockout Mouse At Jackson Lab

June 25, 1997

BAR HARBOR -- A unique mouse model developed by Jackson Laboratory and Canadian researchers exhibits significantly reduced male fertility, suggesting a critical role in reproduction and early embryonic development for the knocked-out gene product known as PC4 (proprotein convertase 4).

The results are reported in the June 24, 1997, issue of Proceedings of the National Academy of Sciences (PNAS) by Majambu Mbikay of the Clinical Research Institute of Montreal at the University of Montreal, Elizabeth M. Simpson of The Jackson Laboratory, and their colleagues. Title of the report is "Impaired Fertility in Mice Deficient for the Testicular Germ-Cell Protease PC4."

PC4 is a member of the proprotein convertase family of serine proteases that function in mammals to mature a variety of precursor proteins -- including prohormones, proneuropeptides, cell surface receptors, and viral surface glycoproteins -- into peptides and bioactive proteins that modulate cell growth and differentiation in development.

Although some of the seven known proprotein convertases have been found to be ubiquitously expressed in the tissues of rodents and mice, PC4 has only been detected in testicular germ cells. That limited expression made PC4 a logical candidate for developing the first mouse mutant with a deficiency in a proprotein convertase. The researchers disrupted the PC4 locus (Pcsk4) by homologous recombination in embryonic stem cells to produce mice carrying the mutation.

The results reported in PNAS suggest that PC4 in the male may be important for achieving fertilization and for supporting early embryonic development in mice. Several precursor proteins, or glycoproteins, are produced in spermatocytes and spermatids, and one theory is that possible failure by PC4-deficient testicular germ cells to properly process those proteins may render them incompetent for fertilization.

Co-authors of the PNAS report include Haidy Tadros, Andrew Chen, Nabil G. Seidah, and Michel Chretien, Clinical Research Institute of Montreal, University of Montreal; Norito Ishida, Eve de Lamirande, and Claude Gagnon, Urology Research Laboratory, McGill University, Montreal; Mohamed El-Alfy and Yves Clermont, Department of Anatomy, McGill University; and Charlie P. Lerner, The Jackson Laboratory.

Jackson Laboratory

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