Hearing loss is the most common sensory deficit and can be present at any time from infancy to old age. About 1 in 300 infants suffer from profound hearing impairment, with half of genetic origin. Many deafness genes encode proteins which are expressed in the sensory hair cells of the inner ear. Hair cells have a specialized structure on their apical surface, the hair bundle. Stimulation of the hair bundle by mechanical deflection leads to modulation of a graded receptor potential via activation of mechanosensitive ion channels. The receptor potential, in turn, modulates neurotransmission and afferent fiber firing patterns.
In my lab, we are elucidating how hair cells acquire the remarkable functions of mechanotransduction and sensory signaling and how genetic mutations impair normal development and survival of sensory hair cells.
My projects are driven by the need to:
1. Establish the fundamentals of normal hair-cell development. Knowledge of how and when hair cells begin to function is critical for understanding development of the auditory and vestibular systems as a whole.
2. Provide an understanding of the etiology of hair-cell specific congenital disorders that affect the auditory and vestibular function. Studying the outcome of deafening mutations, I hope to identify the function of genes suspected to have an important role during the development of the sensory organs of the inner ear.
3. To identify candidate molecules that contribute to essential hair cell functions we have identified temporal correlations between physiological expression patterns and expression patterns of hair cell genes. To test hypotheses generated based on these correlations we examine hair cells of mice that carry naturally occurring mutations, as well as transgenic animals including, targeted gene deletions and targeted gene replacements with mutant genes. In addition, we have pioneered the use of adenoviral vectors to drive expression of dominant-negative constructs to suppress the function of endogenous hair cell proteins; overexpression of wild-type genes to rescue mutant phenotypes and expression of tagged constructs to facilitate protein localization. To assay for changes in function we image FM1-43 uptake, an indicator of functional mechanotransduction, and use the whole-cell, tight-seal recording technique in voltage-clamp mode to record transduction currents or voltage-dependent currents. We use a fast piezoelectric bimorph with a submillisecond rise-time to evoke hair bundle deflections. In current-clamp mode we record membrane potential to examine the functional consequences of altered gene and protein expression.
4. To control gene expression in vivo, we are also currently developing a novel mouse model that will allow inducible, reversible gene expression in hair cells using the lac operator-repressor system (Cronin et al., 2001). If successful, the approach will allow for hair cell-specific, regulatable gene expression at any time point during the lifetime of the mouse, from embryonic stages to late adulthood. This mouse will be a valuable tool for understanding gene function during development and may also serve as a model for studies of age-related hearing loss.
About Gwenaëlle Géléoc
Gwenaëlle Géléoc received a PhD, in 1996, from the University of Montpellier II, France. During her PhD, she worked in collaboration with Drs. Corne Kros and Guy Richardson at the University of Sussex in Brighton, UK. She completed a postdoctoral fellowship in the Department of Physiology at University College London with Professor Jonathan Ashmore and subsequently worked as a postdoctoral fellow with Professor David Corey in the Department of Neurobiology at Harvard Medical School. In 2001, she joined the faculty at the University Of Virginia as Assistant Professor of Research and was promoted to Associate in 2007. In the summer of 2011, she returned to Boston and joined the Department of Otolaryngology at Boston Children’s Hospital and Harvard Medical School in the F.M. Kirby Neurobiology Center.