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-β1 (TGF-β₁) protein. METHODS: In this study, the effects of a teratogenic level of atRA on levels and patterns of expression of TGβF receptor II (TGFβRII) and Smad2, a downstream component of the TGFβ signal transduction pathway, are investigated in the developing mouse inner ear. The expression pattern of endogenous RA receptor α (RARα) and the ability of an RARα₁-specific antisense oligonucleotide (AS) to modulate otic capsule chondrogenesis are demonstrated in the inner ear and in culture. RESULTS: Endogenous TGFβRII and Smad2 are downregulated in the inner ear following in utero atRA treatment. In addition, a reduction in endogenous TGFβ₁ and a marked suppression of chondrogenesis occur in RARα₁ AS-treated cultures in comparison to untreated or oligonucleotide-treated control cultures. This chondrogenic suppression can be partially overcome by supplementation of RARα₁ AS-treated cultures with exogenous TGFβ₁ protein. CONCLUSIONS: Our findings support a role for TGFβ in the physiological and pathological effects of RA on inner ear development.