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

Abstract

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.

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

“…Furthermore, in both cartilage and epithelia there is an association between IHH and hormonal regulation. In mouse uterus, IHH mediates epithelial-mesenchymal interactions and is regulated by progesterone (62,63). IHH is also expressed in mammary gland epithelium and is up-regulated during pregnancy and lactation (64).…”

Animal models of implantation

“…In the past decade, the use of gene expression screening techniques, including microarray analysis, has begun to identify factors whose expression is stimulated by P4. A few of these target genes that have been shown to have functional significance in implantation include calcitonin (Ding et al 1994), Indian hedgehog (IHH) (Takamoto et al 2002), and amphiregulin (Ar) (Das et al 1995). Intraluminal injection of antisense oligonucleotides to calcitonin into the rat uterus leads to drastically reduced numbers of implantation sites (Zhu et al 1998).…”

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

“…P 4 signaling inhibits the estrogen signaling pathways in the uterus (Hsueh et al 1975) and this inhibitory relationship involving both hormone pathways orchestrate the regulatory mechanisms required for endometrial receptivity and embryo implantation. Amongst the regulated transcripts in the mid-secretory endometrium from women with mifepristone administration we found several genes involved in the P 4 signaling axis including modulators and effectors with down regulation of NCOA2 (SRC-2, (Mukherjee et al 2006, Jeong et al 2007), IHH (Matsumoto et al 2002, Takamoto et al 2002, ERRFI1 (MIG6, (Kim et al 2010)) PTCH1 (Lee et al 2006) and DKK1 ; and up-regulation of ESR1 (Curtis et al 1999), PRA (Conneely & Lydon 2000), FKBP5 (Tranguch et al 2005), FOXO1A (Kim et al 2005), KLF9 (Simmen et al 2004) and PTGS1 (Wang et al 2004).…”