Project Summary
Hearing loss is a potentially debilitating condition that afflicts to varying extents more than 30 million
individuals in the United States. Commonly caused by destruction of the mechanosensory hair cells in
the inner ear, most hearing loss in humans is permanent because these cells are not naturally
replenished. Unlike those in the human ear, hair cells of non-mammalian vertebrates including fishes,
amphibians, and reptiles including birds can regenerate throughout life. Despite extensive research, the
molecular and cellular bases of this difference are not yet well understood. Because a more complete
comprehension of hair-cell regeneration in non-mammalian model systems will foster the development
of regenerative therapies for hearing loss, our current research focuses on elucidating the mechanism of
hair-cell regeneration in one such system, the zebrafish lateral line. The lateral line comprises an array
of superficially located hair cell-containing organs called neuromasts that detect water displacement.
We have devised procedures for transgenically labeling and isolating the putative progenitors—called
mantle cells—that are thought to give rise to hair cells in neuromasts during regeneration. Microarray
analysis has revealed numerous genes that are highly and specifically expressed in mantle cells, as well
as genes whose expression in these cells is modulated in response to ototoxic insult. The resulting data
set places us in a unique position to determine which molecular pathways activate or repress the
proliferation of progenitors and the subsequent replacement of hair cells. Among the top candidate
genes for controlling progenitor proliferation are those encoding the transmembrane protein Tspan1
and the protocadherins Fat1a and Fat1b, which are highly enriched in mantle cells and are down-
regulated during regeneration. We propose to use loss-of-function (antisense-mediated knockdown
and existing mutant lines) as well as gain-of-function (mRNA-mediated overexpression and
misexpression by means of an inducible transgenic system) to test the functions of Tspan1, Fat1a, and
Fat1b in hair-cell development and regeneration. Through these studies we hope to uncover previously
unappreciated molecular mechanisms governing hair-cell regeneration, which may contribute to the
future development of therapies for hearing loss.
