title: Dominant activation of the hedgehog signaling pathway alters development of the female reproductive tract.
abstract: The role of hedgehog (HH) signaling in reproductive tract development was studied in mice in which a dominant active allele of the signal transducer smoothened (SmoM2) was conditionally expressed in the Müllerian duct and ovary. Mutant females are infertile, primarily because they fail to ovulate. Levels of mRNA for targets of HH signaling, Gli1, Ptch1, and Hhip, were elevated in reproductive tracts of 24-day-old mutant mice, confirming overactivation of HH signaling. The tracts of mutant mice developed abnormally. The uterine luminal epithelium had a simple columnar morphology in control mice, but in mutants contained stratified squamous cells typical of the cervix and vagina. In mutant mice, the number of uterine glands were reduced and the oviducts were not coiled. Expression of genes within the Hox and Wnt families that regulate patterning of the reproductive tract were altered. Hoxa13, which is normally expressed primarily in the vagina and cervix, was expressed at 12-fold higher levels in the uterus of mutant mice compared with controls. Wnt5a, which is required for development of the cervix and vagina and postnatal differentiation of the uterus, was expressed at higher levels in the oviduct and uterus of mutant mice compared with controls. Mating mutant females with fertile or vasectomized males induced a severe inflammatory response in the tract. In summary, overactivation of HH signaling causes aberrant development of the reproductive tract. The phenotype observed could be mediated by ectopic expression of Hoxa13 in the uterus and elevated levels of Wnt5a in the oviducts and uterus.
authors.affiliation: Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Migone
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cowan
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Harman
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Nikitin
authors.forename: Susan M
authors.initials: SM
authors.lastname: Quirk
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009095:Mullerian Ducts / Q000378:metabolism; D009154:Mutation; D010053:Ovary / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012098:Reproduction / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014599:Uterus / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C099959:homeobox protein HOXA13