The vertebrate inner ear develops from a simple piece of embryonic ectoderm called the otic placode to form one of the most complex sensory organs in the animal kingdom. The mammalian inner ear contains six groups of mechanosensory hair cells, five of which mediate our sense of balance (detecting linear and angular acceleration), and the sixth – the organ of Corti – detects sound. We are interested in the signals and transcriptional regulators that single out tissue destined to form the otic placode, and which sculpt its descendants to form a morphologically complex structure that generates the precise numbers of cells at the right time. We have identified a transcription factor, Foxi3, that appears to be expressed in the progenitors of all craniofacial placodes, and which is necessary for the entire inner ear to form. We are also investigating how signaling pathways such as Notch, BMPs and Wnts contribute to the intricate pattern of the inner ear.

We detect sound and balance information with exquisitely sensitive hair cells, which get their name from the hair-like bundle of actin-rich stereovilli that protrude from their apical surface. These cells are capable of detecting mechanical deflections at the sub-nanometer range, but with their great sensitivity comes great vulnerability. Hair cells can be killed by loud noise, the aging process, and certain drugs such as aminoglycoside antibiotics and platinum-containing chemotherapy drugs. Mammals, including humans, are unable to regenerate their hair cells after they are killed. However, other vertebrates such as birds, amphibians and fish are capable of mobilizing supporting cells to divide and transdifferentiate to hair cells, restoring both hearing and balance. We are trying to understand the roadblocks to hair cell regeneration in mammals, and how these blocks appear in the early life of mammals. We are experimenting with gene therapy and reprogramming strategies to try and promote hair cell regeneration and haring restoration in mammals.

Finally, we are interested in how mechanosensory hair cells arose during evolution. We are analyzing the transcriptional signatures of mechanosensory cells that detect sound or balance in fruit flies, cephalopods (squid) and our closest invertebrate relatives, the tunicates (or sea squirts), and comparing them with those of vertebrate hair cells. We hope to identify core gene and protein regulatory networks that are conserved during the evolution of mechanosensory cells.

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