title: Transforming growth factor-beta1 signaling participates in the physiological and pathological regulation of mouse inner ear development by all-trans retinoic acid.
abstract: BACKGROUND
  Retinoic acid (RA) is a vitamin A derivative that participates in patterning and regulation of inner ear development. Either excess RA or RA deficiency during a critical stage of inner ear development can produce teratogenic effects. Previous studies have shown that in utero exposure of the developing mouse inner ear to a high dose of all-trans RA (atRA) results in severe malformations of the inner ear that are associated with diminished levels of endogenous transforming growth factor-beta1 (TGF-beta(1)) protein.
  
  
  METHODS
  In this study, the effects of a teratogenic level of atRA on levels and patterns of expression of TGFbeta receptor II (TGFbetaRII) and Smad2, a downstream component of the TGFbeta signal transduction pathway, are investigated in the developing mouse inner ear. The expression pattern of endogenous RA receptor alpha (RARalpha) and the ability of an RARalpha(1)-specific antisense oligonucleotide (AS) to modulate otic capsule chondrogenesis are demonstrated in the inner ear and in culture.
  
  
  RESULTS
  Endogenous TGFbetaRII and Smad2 are downregulated in the inner ear following in utero atRA treatment. In addition, a reduction in endogenous TGFbeta(1) and a marked suppression of chondrogenesis occur in RARalpha(1) AS-treated cultures in comparison to untreated or oligonucleotide-treated control cultures. This chondrogenic suppression can be partially overcome by supplementation of RARalpha(1) AS-treated cultures with exogenous TGFbeta(1) protein.
  
  
  CONCLUSIONS
  Our findings support a role for TGFbeta in the physiological and pathological effects of RA on inner ear development.
authors.affiliation: Department of Otolaryngology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
authors.forename: Sydney C
authors.initials: SC
authors.lastname: Butts
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Geming
authors.initials: G
authors.lastname: Li
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Frenz
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D007758:Ear, Inner / Q000002:abnormalities* / Q000187:drug effects* / Q000196:embryology; D004848:Epithelium / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008648:Mesoderm / Q000276:immunology; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000633:toxicity*
chemical_list: D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D018125:Receptors, Transforming Growth Factor beta; D000072482:Retinoic Acid Receptor alpha; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II