Activity and retinoic acid drive hair cell spatial patterning in the zebrafish utricle

The zebrafish vestibular otolith organs, like those of other vertebrate
species, are organized into central (striolar) and peripheral
(extrastriolar) zones that drive different vestibular circuits. How and
when these hair cell patterns develop in the zebrafish is unknown. We
determined that early-developing hair cells (<36 hours) expressed
both striolar and extrastriolar transcriptomic markers. After 36 hours,
these hair cells specify into extrastriolar hair cells. Later-developing
hair cells (>36 hours) mostly develop directly as striolar or
extrastriolar. We observed complementary patterns of RA degrading and
synthesizing enzymes that colocalize with striolar and extrastriolar
zones, respectively, suggesting evolutionarily conserved molecular
signaling. RA treatment during development increased the relative
proportion of extrastriolar and intermediate-type hair cells, indicating
that enriched RA reduces striolar development. However, in fish with
mechanotransduction dysfunction from a cdh23 mutation, normal RA
patterning is insufficient to finalize the fate of early-born hair cells,
which remain transcriptomically unresolved. RA treatment further
exacerbates abnormal patterning. Therefore, we conclude that hair cell
fate, and thus normal zonal patterning, depends on both hair cell activity
and the RA gradient.