Effect of retinoic acid on otic capsule chondrogenesis in high-density culture suggests disruption of epithelial-mesenchymal interactions.
Previous studies have shown that in utero exposure of the mouse embryo to nonphysiological levels of all-trans retinoic acid (RA) produces malformations of the epithelial-derived auditory and vestibular receptors of the inner ear and its surrounding cartilaginous capsule. In this study, we demonstrate the effects of all-trans RA in high-density cultures of the periotic mesenchyme fated to form the otic capsule. Our results demonstrate an inhibition of chondrogenesis in cultured periotic mesenchyme + otic epithelium of embryonic age E10.5 days (E10.5) in response to all-trans RA exposure. However, at later stages of development (i.e., E12, E14), when epithelial-mesenchymal interactions are no longer required for initiation of chondrogenesis, exposure to this teratogen has no effect on the chondrogenic process. Two analogues of all-trans RA, i.e., cis-RA and trans-retinol, were investigated for their biological activity in chondrogenic cultures of inner ear mesenchyme + epithelium. Moreover, we tested the inductive capability and responsiveness of in utero RA-exposed inner ear tissues when cultured with inner ear tissues that were not exposed to this teratogen. Our results support the hypothesis that all-trans RA disrupts otic capsule formation by interfering with the tissue interactions required for its normal differentiation and development.
Frenz
D A
DA
Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Liu
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects; D011247:Pregnancy; D014212:Tretinoin / Q000031:analogs & derivatives / Q000633:toxicity*
D000970:Antineoplastic Agents; D014212:Tretinoin; D003094:Collagen