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Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility¹

Prince Henry's Institute of Medical Research,⁴ Clayton, Victoria 3168, Australia State Key Laboratory for Reproductive Biology,⁵ Institute of Zoology, Chinese Academy of Sciences, Beijing, 100080 China

Successful embryo implantation involves complex interactions between the embryo and the uterus and is critical in establishing pregnancy. Proprotein convertase (PC) 6 (PC6) is one of the PC endoproteases regulating protein function through posttranslational activation of precursor proteins, including growth and differentiation factors. Here we show that PC6 protein is induced in the uterine stromal cells specifically at the site of embryo attachment during early pregnancy in mice. In vivo blocking of uterine production of PC6 protein using morpholino antisense oligonucleotides in mice resulted in total inhibition of implantation, revealing a vital role for PC6 in modulating the uterus for embryo implantation. Studies in primates (rhesus monkey and human) showed a dramatic upregulation of endometrial PC6 during the phase of uterine receptivity and at implantation, particularly during a critical uterine cell differentiation process termed decidualization. Thus, the current studies have demonstrated that PC6 is an essential molecule in modulating uterine function to support the establishment of embryo implantation. Interestingly, PC6 is one of the PCs identified to be important in processing the coat protein of HIV; inhibition of PCs has been suggested to be an effective approach to reduce HIV transmission. We therefore propose the novel concept that PC6 could be a potential nonhormonal target in the female reproductive tract for dual protection for women, both in preventing pregnancy and reducing HIV infection.

¹ Supported by the Rockefeller/World Health Organization (WHO) Initiative on Implantation (RF 99021#116), the NH&MRC of Australia (#198705, #143798, and #241000), and NSFC of China (#30270196). M.W. was a WHO-sponsored trainee.

² Correspondence: Guiying Nie, Prince Henry's Institute of Medical Research, P.O. Box 5152, 246 Clayton Rd, Clayton, Victoria 3168, Australia. FAX: 61 3 9594 6125; guiying.nie{at}phimr.monash.edu.au

³ Current address: Shanghai Second Medical University, Shanghai 200025, China