title: Induction of WNT inhibitory factor 1 expression by Müllerian inhibiting substance/antiMullerian hormone in the Müllerian duct mesenchyme is linked to Müllerian duct regression.
abstract: A key event during mammalian sexual development is regression of the Müllerian ducts (MDs) in the bipotential urogenital ridges (UGRs) of fetal males, which is caused by the expression of Müllerian inhibiting substance (MIS) in the Sertoli cells of the differentiating testes. The paracrine signaling mechanisms involved in MD regression are not completely understood, particularly since the receptor for MIS, MISR2, is expressed in the mesenchyme surrounding the MD, but regression occurs in both the epithelium and mesenchyme. Microarray analysis comparing MIS signaling competent and Misr2 knockout embryonic UGRs was performed to identify secreted factors that might be important for MIS-mediated regression of the MD. A seven-fold increase in the expression of Wif1, an inhibitor of WNT/β-catenin signaling, was observed in the Misr2-expressing UGRs. Whole mount in situ hybridization of Wif1 revealed a spatial and temporal pattern of expression consistent with Misr2 during the window of MD regression in the mesenchyme surrounding the MD epithelium that was absent in both female UGRs and UGRs knocked out for Misr2. Knockdown of Wif1 expression in male UGRs by Wif1-specific siRNAs beginning on embryonic day 13.5 resulted in MD retention in an organ culture assay, and exposure of female UGRs to added recombinant human MIS induced Wif1 expression in the MD mesenchyme. Knockdown of Wif1 led to increased expression of β-catenin and its downstream targets TCF1/LEF1 in the MD mesenchyme and to decreased apoptosis, resulting in partial to complete retention of the MD. These results strongly suggest that WIF1 secretion by the MD mesenchyme plays a role in MD regression in fetal males.
authors.affiliation: Vincent Center of Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Vincent Center of Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Nelson A
authors.initials: NA
authors.lastname: Arango
authors.affiliation: Vincent Center of Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: L Andrew
authors.initials: LA
authors.lastname: Benedict
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Mi In
authors.initials: MI
authors.lastname: Roh
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.affiliation: Vincent Center of Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address: jose.teixeira@hc.msu.edu.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Teixeira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009095:Mullerian Ducts / Q000196:embryology* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C422908:Siglece protein, mouse; C118544:Wif1 protein, mouse; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone
keywords: AntiMüllerian hormone; Reproductive tract development; WNT signaling