title: Retinoic acid signaling regulates sonic hedgehog and bone morphogenetic protein signalings during genital tubercle development.
abstract: Retinoic acid (RA) plays pivotal roles in organogenesis, and both excessive and reduced amounts of RA cause developmental abnormalities. Reproductive organs are susceptible to teratogen toxigenicity, and the genital tubercle (GT) is one such representative organ. The physiological function of endogenous RA signaling and the mechanisms of RA-induced teratogenicity are poorly understood during the GT development. The objective of this study is to understand the developmental and teratogenic roles of RA during GT development by analyzing genetically modified mouse models. We found dynamic patterns of gene expression for the RA-synthesizing enzyme, Raldh2, and for the RA-catabolizing enzyme, Cyp26b1, during GT development. Rarb, an indicator gene for RA signaling, starts its expression in the prospective corpus cavernosum penis and in the urethral plate epithelium (UE), which plays central roles during GT development. Excessive RA signaling in Cyp26b1(-/-) mutants leads to abnormal extents of cell proliferation and differentiation during GT development, and also upregulates expression of growth factor signalings. They include Sonic hedgehog (Shh) signaling and Bone morphogenetic protein (Bmp) signaling, which are expressed in the UE and its bilateral mesenchyme. RA signaling positively regulatesShh and Bmp4 expression during GT development as testified also by the experiment of RA administration and analyses of loss-of-function of RA signaling mutants. Thus, RA signaling is involved in the developmental cascade necessary for UE formation and GT development.
authors: Department of Organ Formation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Liqing
authors: L
authors: Liu
authors: Kentaro
authors: K
authors: Suzuki
authors: Naomi
authors: N
authors: Nakagata
authors: Kenichiro
authors: K
authors: Mihara
authors: Daisuke
authors: D
authors: Matsumaru
authors: Yukiko
authors: Y
authors: Ogino
authors: Kenta
authors: K
authors: Yashiro
authors: Hiroshi
authors: H
authors: Hamada
authors: Zhonghua
authors: Z
authors: Liu
authors: Sylvia M
authors: SM
authors: Evans
authors: Cathy
authors: C
authors: Mendelsohn
authors: Gen
authors: G
authors: Yamada
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005835:Genitalia / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014212:Tretinoin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase