Retinoic Acid Signaling Regulates Sonic Hedgehog and Bone Morphogenetic Protein Signalings During Genital Tubercle Development

Liqing Liu, Kentaro Suzuki, Naomi Nakagata, Kenichiro Mihara, Daisuke Matsumaru, Yukiko Ogino, Kenta Yashiro, Hiroshi Hamada, Zhonghua Liu, Sylvia M. Evans, Cathy Mendelsohn, Gen Yamada

研究成果: Contribution to journalArticle査読

19 被引用数 (Scopus)


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.

ジャーナルBirth Defects Research Part B - Developmental and Reproductive Toxicology
出版ステータス出版済み - 2 2012

All Science Journal Classification (ASJC) codes

  • 胎生学
  • 毒物学
  • 発生生物学
  • 健康、毒物学および変異誘発


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