The retinoic acid receptors RARα and RARγ are required for inner ear development

To define the signal transduction pathway of retinoic acid during inner ear development, we analyzed the expression patterns of transcripts encoding the three retinoic acid receptors (RARa, b, and g) and related them to phenotypes resulting from single or compound inactivation of these nuclear receptors. The expression of all three RARs was observed in the developing mouse otocyst as early as embryonic day 10.5 (E10.5)–E12.5 and continued into adulthood. Expression domains of the three RAR receptors, however, were largely non-overlapping: RARa was predominantly expressed in the developing sensory epithelium, RARb in inner ear mesenchymal tissues and RARg in the differentiating otic capsule. In the adult, RARa and RARg transcripts were found in the organ of Corti and the spiral ganglion, whereas RARb transcripts were localized in mesenchyme-derived tissues. RARa,b, andg null mutant mice, as well as RARa/RARb and RARb/RARg combined null fetuses, did not present any noticeable morphological abnormalities in the inner ear. In contrast, RARa/RARg null mutants displayed a severe hypoplasia of the otocyst that was already visible at E10.5 without any visible endolymphatic duct. The hypoplastic otocyst in RARa/ RARg null mutants was characterized by impaired chondrocyte differentiation and neural development. After the second week of gestation, these mutant fetuses lacked all of the semi-circular canals and the endolymphatic duct and displayed strong anomalies in the inner ear structures. The morphological deficits were generally more severe in the cochlear portion than in the vestibular portion of the inner ear. Altogether, these results demonstrate that RARa and RARg play an essential role in the initial differentiation of otic placode derivatives, whereas RARb plays a minimal role in this process. q 2002 Elsevier Science Ireland Ltd. All rights reserved.