title: Parturition failure in mice lacking Mamld1.
abstract: In mice, the onset of parturition is triggered by a rapid decline in circulating progesterone. Progesterone withdrawal occurs as a result of functional luteolysis, which is characterized by an increase in the enzymatic activity of 20α-hydroxysteroid dehydrogenase (20α-HSD) in the corpus luteum and is mediated by the prostaglandin F2α (PGF2α) signaling. Here, we report that the genetic knockout (KO) of Mamld1, which encodes a putative non-DNA-binding regulator of testicular steroidogenesis, caused defective functional luteolysis and subsequent parturition failure and neonatal deaths. Progesterone receptor inhibition induced the onset of parturition in pregnant KO mice, and MAMLD1 regulated the expression of Akr1c18, the gene encoding 20α-HSD, in cultured cells. Ovaries of KO mice at late gestation were morphologically unremarkable; however, Akr1c18 expression was reduced and expression of its suppressor Stat5b was markedly increased. Several other genes including Prlr, Cyp19a1, Oxtr, and Lgals3 were also dysregulated in the KO ovaries, whereas PGF2α signaling genes remained unaffected. These results highlight the role of MAMLD1 in labour initiation. MAMLD1 likely participates in functional luteolysis by regulating Stat5b and other genes, independent of the PGF2α signaling pathway.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Miyado
authors.affiliation: Department of Reproductive Biology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Miyado
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Momori
authors.initials: M
authors.lastname: Katsumi
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Reproductive Biology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Daizou
authors.initials: D
authors.lastname: Shihara
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D000818:Animals; D002460:Cell Line; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000378:metabolism; D036801:Parturition; D011247:Pregnancy; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C577863:Mamld1 protein, mouse; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D014157:Transcription Factors; D004960:Estradiol Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme