The Differential Sensitivities of Inner Ear Structures to Retinoic Acid during Development

Abstract

In order to examine the mechanisms that underlie development of the inner ear, the normal processes were perturbed using all-trans-retinoic acid (RA). By implanting a resin exchange bead saturated with RA into stage 16 (Hamburger and Hamilton, 1951, J. Morphol. 88, 49-92) embryonic day 2.5 chick ears, it was possible to analyze its in vivo effects on inner ear development. There is a temporal window during which the developing chick inner ear is particularly susceptible to the effects of RA (stages 16-19). This RA period of sensitivity precedes evidence of gross morphologic or histologic differentiation by at least 24 h, suggesting that mechanisms controlling formation of key inner ear structures are already in progress. There is a dose dependence on RA, with increasing doses of RA generating increasingly severe phenotypic abnormalities. Data indicate that these effects are due to differential sensitivities of the various inner ear structures to RA during their formation. In general, the vestibular structures were more susceptible to RA effects than the cochlear duct. Furthermore, nonsensory structures such as semicircular canals seemed to display a greater susceptibility to RA than their associated sensory structures (i.e., cristae). Among the three semicircular canals, the superior canal was the most susceptible to RA treatment, whereas the common crus was particularly resistant, suggesting that the molecular mechanisms for each structure's formation are different. The defect in semicircular canal formation is due to problems in the initial outgrowth of the canal plate which in turn is related to a down-regulation of early otocyst cell proliferation. This perturbation model provides valuable insight into the processes involved in producing the intricate patterning of the inner ear.

Retinoic Acid Repression of Bone Morphogenetic Protein 4 in Inner Ear Development

“…These abnormalities closely resemble the human ear anomalies known as Michel aplasia and the Mondini-Alexander defect (4). Chicken otocysts implanted with at-RA-saturated beads exhibited several types of malformations, ranging from the absence of SCCs to a phenotype exhibiting only a rudimentary inner ear mass (6). Thus, the malformations due to excess at-RA resemble the malformations observed when BMP4 action is antagonized by noggin, suggesting that at-RA and BMP4 function through the same pathway to regulate SCC development.…”

“…Control CHO cells or BMP4 CHO cells were placed on Cibacron beads (Sigma) and implanted into the center of stage 16 to 17 otocysts as previously described (10). at-RA beads were prepared as previously described (6). Briefly, a 100-l volume of AG1X-8 beads resuspended in DMSO was pelleted and then resuspended in 0.125 mg of at-RA per ml of DMSO (or in plain DMSO as a control).…”

“…Thus, the malformations due to excess at-RA resemble the malformations observed when BMP4 action is antagonized by noggin, suggesting that at-RA and BMP4 function through the same pathway to regulate SCC development. Furthermore, when chicken otocysts were implanted with at-RA-saturated beads, BMP4 expression decreased in the developing anterior crista (6). However, it is not known whether this was a direct effect of at-RA or whether it was causally related to the subsequent SCC abnormalities.…”

The development of semicircular canals in the inner ear: role of FGFs in sensory cristae

“…Although low levels or absence of FGF activity is required to specify or maintain a common crus fate, FGF is unlikely to be the only factor required for this fate. Regulated levels of BMPs are important (see below), and insensitivity to retinoic acid might also be involved because the common crus is particularly resilient to retinoic acid treatments (Choo et al, 1998). In addition, blocking FGF activity with SU5402 is insufficient to recruit the surrounding canal pouch epithelium to form an ectopic common crus (Fig.…”

The effects of oral isotretinoin (13-Cis retinoic acid) on the inner ear: A prospective clinical study

“…Other research has suggested that the development of the inner ear structures depends on retinoid signalling via the retinoic acid receptors [10]. e embryologic inner ear is sensitive to the e ects of retinoids for a limited period of [11]. During this period, either a de ciency or excess of vitamin A can cause malformations [10].…”