Transforming growth factor-β1 signaling participates in the physiological and pathological regulation of mouse inner ear development by all-trans retinoic acid

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-beta 1 (TGF-beta(1)) protein. METHODS: In this study, the effects of a teratogenic level of atRA on levels and patterns of expression of TGF beta receptor II (TGF beta RII) and Smad2, a downstream component of the TGF beta signal transduction pathway, are investigated in the developing mouse inner ear. The expression pattern of endogenous RA receptor a (RAR alpha) and the ability of an RAR alpha(1)-specific antisense oligonucleotide (AS) to modulate otic capsule chondrogenesis are demonstrated in the inner ear and in culture. RESULTS: Endogenous TGF beta RII and Smad2 are downregulated in the inner ear following in utero atRA treatment. In addition, a reduction in endogenous TGF beta(1) and a marked suppression of chondrogenesis occur in RAR alpha(1) AS-treated cultures in comparison to untreated or oligonucleotide-treated control cultures. This chondrogenic suppression can be partially overcome by supplementation of RAR alpha(1) AS-treated cultures with exogenous TGF beta(1) protein. CONCLUSIONS: Our findings support a role for TGF beta in the physiological and pathological effects of RA on inner ear development. Birth Defects Research (Part A) 73: 218-228, 2005. 2005 Wiley-Liss, Inc.