Transforming growth factor-?1 signaling participates in the physiological and pathological regulation of mouse inner ear development by all-trans retinoic acid

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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-β1 (TGF-β1) protein. METHODS In this study, the effects of a teratogenic level of atRA on levels and patterns of expression of TGFβ 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. Birth Defects Research (Part A), 2005.