Neuronal development, regeneration, physiology
1. Regulation of inner ear (cochlear) development and regeneration.
The organ of Corti (OC) is a complex mechanosensory structure that transduces sound vibrations into neuronal signals. The OC contains one row of inner hair cells (IHC) and three rows of outer hair cells (OHCs), separated by pillar cells (PCs). In addition, each sensory hair cell is associated with an underlying supporting cell (SC). The mechanisms that regulate the formation of OHCs are significant, since the loss of OHCs is a leading cause of sensorineural deafness and age-related hearing loss.
We have found that mice lacking a functional FGF20 gene are viable and healthy but are congenitally deaf. Developmental analysis showed that FGF20 is required for outer hair cell differentiation and that FGF20 together with its paralog, FGF9, is required for sensory progenitor cell proliferation.
Our aims are to identify the molecular mechanisms that regulate the expression of Fgf20 during the embryonic development of the cochlea; to determine how FGF20 regulates sensory progenitor cell growth and the differentiation of cochlear outer hair and supporting cells in the organ of Corti; and to identify the specific genes and pathways that act downstream of FGF20 during cochlear development using Next Gen mRNA sequencing. We are testing the hypothesis that FGF signaling can enhance sensory cell regeneration following ototoxic damage.
2. Regulation of neuronal excitability by intracellular FGFs.
We are studying a unique subfamily of FGFs that act intracellularly (iFGFs) in neurons and cardiomyocytes and that are important for regulating cell excitability through interactions with voltage gated sodium channels. Disruption of FGF14, one of four iFGFs, results in an anatomically normal mouse with severe neurobehavioral phenotypes including ataxia, seizure, paroxysmal dystonia and cognitive impairment. A mutation in FGF14 in humans is the cause of a dominant progressive spinocerebellar ataxia syndrome, SCA27. We are investigating the role of FGF14 as a regulator of neuronal excitability, the mechanism of action of the SCA27 mutation in FGF14, and the role of FGF14 as an intracellular regulator of voltage gated sodium channel function.