title: Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation.
abstract: Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Numata
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Dennis Diana
authors.initials: DD
authors.lastname: Raga
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Lerrie Ann
authors.initials: LA
authors.lastname: Ipulan
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Chikako
authors.initials: C
authors.lastname: Yokoyama
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan;
authors.forename: Shoko
authors.initials: S
authors.lastname: Matsushita
authors.affiliation: Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan; and.
authors.forename: Michito
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development, and.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: Departments of Kidney Development and.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.affiliation: Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
authors.affiliation: Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan; and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), 811-1 Kimiidera, Wakayama 641-8509, Japan; genyama77@yahoo.co.jp.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
mesh_terms: D000728:Androgens / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005836:Genitalia, Female / Q000196:embryology / Q000378:metabolism; D005837:Genitalia, Male / Q000196:embryology* / Q000378:metabolism; D007021:Hypospadias / Q000196:embryology / Q000235:genetics; D051258:MafB Transcription Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000172:deficiency / Q000502:physiology; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000502:physiology*; D014521:Urethra / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism
chemical_list: D000728:Androgens; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D011944:Receptors, Androgen
keywords: Mafb; androgen receptor; hypospadias; masculinization; urethra