DEVELOPMENTAL REGULATION OF FOS-PROTEIN DURING PROLIFERATIVE GROWTH OF THE OTIC VESICLE AND ITS RELATION TO DIFFERENTIATION-INDUCED BY RETINOIC ACID

This work studies Fos protein expression in the otic vesicle and the developing cochleovestibular ganglion (CVG), focusing on the possible role of Fos in the regulation of cell proliferation and differentiation during otic development. Fos was detected as a product of 56-62 kDa in otic vesicles and CVG lysates. Expression was transient and stage-dependent. Maximal levels occurred at stage 20 in the otic vesicle and at Day 4 in the CVG. Another wave of Fos expression occurred after Day 7 of development, out of the early proliferative period. Fos immunoreactivity was localized in cell nuclei of otic epithelium and CVG. Fos was readily induced by mitogens like serum and bombesin and this induction was inhibited by 25 nM retinoic acid, an inhibitor of cell proliferation in the otic vesicle. c-fos antisense oligonucleotides inhibited growth in the otic vesicle in parallel with a reduction in Fos expression. High levels of Fos protein were not sufficient, however, to sustain growth of isolated otic vesicles in the absence of mitogens. Incubation with retinoic acid (24 hr) induced differentiation of sensory hair-cells in parallel with inhibition of cell proliferation. Contrary to retinoic acid, Fos inhibition by antisense did not induce differentiation. The results suggest that Fos is part of the signaling mechanisms regulating normal development of the inner ear. Regulation of Fos may be required for controlling of the transition between cell proliferation and differentiation. (C) 1995 Academic Press, Inc.