Identification of Indian Hedgehog as a Progesterone-Responsive Gene in the Murine Uterus

Progesterone (P4) plays a central role in normal uterine function, from embryo implantation in endometrium to establishment and maintenance of uterine quiescence during pregnancy in the myometrium. Considering its diverse physiological effects on female reproductive function, rather little is known about downstream events of P4 action. Recent progress in differential screening technologies facilitated identification of such inducible genes. We used uteri of wild-type and progesterone receptor null mutant mice as a starting material and screened for differentially expressed genes by medium-density cDNA expression array. Here, we report that the expression of the morphogen, Indian hedgehog (Ihh), is rapidly stimulated by P4 in the mouse uterus. The level of Ihh mRNA is induced within 3 h, after a single administration of P4 to ovariectomized mice. The induced Ihh mRNA and protein were localized to the luminal and glandular epithelial compartment of the endometrium. During pseudopregnancy, the Ihh mRNA level was transiently increased in the preimplantation period and d 3 and d 4 post coitum and then decreased rapidly at d 5 post coitum. Furthermore, the expression profile of patched-1, hedgehog interacting protein-1, and chicken ovalbumin upstream promoter-transcription factor II, genes known to be in the hedgehog signaling pathway in other tissues, followed the expression pattern of Ihh during the periimplantation period. Our results suggested that Ihh is regulated by P4, and the Ihh signaling axis may play a role in the preparation of the uterus for implantation during the periimplantation period.