Retinoid signaling in inner ear development: A "Goldilocks" phenomenon.
Retinoic acid (RA) is a biologically active derivative of vitamin A that is indispensable for inner ear development. The normal function of RA is achieved only at optimal homeostatic concentrations, with an excess or deficiency in RA leading to inner ear dysmorphogenesis. We present an overview of the role of RA in the developing mammalian inner ear, discussing both how and when RA may act to critically control a program of inner ear development. Molecular mechanisms of otic teratogenicity involving two members of the fibroblast growth factor family, FGF3 and FGF10, and their downstream targets, Dlx5 and Dlx6, are examined under conditions of both RA excess and deficiency. We term the effect of too little or too much RA on FGF/Dlx signaling a Goldilocks phenomenon. We demonstrate that in each case (RA excess, RA deficiency), RA can directly affect FGF3/FGF10 signaling within the otic epithelium, leading to downregulated expression of these essential signaling molecules, which in turn, leads to diminution in Dlx5/Dlx6 expression. Non-cell autonomous affects of the otic epithelium subsequently occur, altering transforming growth factor-beta (TGFβ) expression in the neighboring periotic mesenchyme and serving as a putative explanation for RA-mediated otic capsule defects. We conclude that RA coordinates inner ear morphogenesis by controlling an FGF/Dlx signaling cascade, whose perturbation by deviations in local retinoid concentrations can lead to inner ear dysmorphogenesis.
Department of Otorhinolaryngology Head & Neck Surgery, Albert Einstein College of Medicine, Bronx, New York, USA. dorothy_frenz@nymc.edu
Dorothy A
DA
Frenz
Wei
W
Liu
Ales
A
Cvekl
Qing
Q
Xie
Lesley
L
Wassef
Loredana
L
Quadro
Karen
K
Niederreither
Mark
M
Maconochie
Alan
A
Shanske
D000818:Animals; D002450:Cell Communication / Q000235:genetics; D007758:Ear, Inner / Q000002:abnormalities / Q000196:embryology*; D004622:Embryo, Mammalian; D004848:Epithelium / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D005346:Fibroblast Growth Factors