Protein sorting in the maturation of inner ear cells

Lead Research Organisation: University College London
Department Name: Ear Institute



Our ability to hear a vast range of sounds relies on thousands of specialised sensory receptors inside the auditory part of the ear. These "hair cells" are also found in balance organs within the inner ear, where they allow us to sense movements of our head and appreciate the effects of gravity. Errors in the development of these cells are associated with hearing loss and balance deficits found in a number of diseases, and progressive loss of hair cells most likely contributes to the majority of cases of age-related hearing loss and falls in the elderly.

Hair cells bear a mechanically sensitive apparatus, known as the "hair bundle", and this delicate structure must be placed in the right place and in the correct orientation to be most sensitive to the microscopic fluid movements provided by sound and head movements. This process is instructed by numerous interacting genes, and variations in these genes can cause forms of inherited hearing loss and balance problems that contribute to complex syndromes. It is not currently understood how the essential building blocks and signalling molecules that are involved in building the bundle are directed to be in the right place in hair cells, at the right time.

This project has several goals. We wish to determine how the complexity of hair bundle shape and orientation is regulated at a molecular level during normal development, and how this regulation is affected under conditions during certain diseases of the nervous system. We aim to find out how essential proteins are delivered to specific regions of a hair cell. We want to know if this protein sorting pathway contributes to ongoing replacement of hair cells and repair after damage to the inner ear. Finally, we want to know if a molecular regulator of hair bundle shape during embryonic development can subsequently play quite distinct roles in support of the functionally mature inner ear.

Our studies would provide a detailed analysis of mechanisms contributing to the normal development of the inner ear, explain how these mechanisms are affected by genetic disease, and how they may be harnessed in the future in order to repair the inner ear following damage or during old age, by replacing lost hair cells or by prolonging their lifespan. These mechanisms are likely to be important in other regions of the nervous system, and so our results will be of wider importance, and may contribute to future treatments of neural disorders.

Technical Summary

Technical summary

The morphogenesis of the hair cell stereociliary bundle in mice depends on the interaction of several signalling pathways, including long-distance planar cell polarity (PCP) and a cell-autonomous mechanism that regulates the apical cytoskeleton. The correct subcellular targeting of a "polarity complex" of key proteins results in a specific migration of the primary cilium, and the graded lengthening of individual stereocilia. Deletion of the genes coding for these proteins results in malformed and stunted bundles. In recent work we revealed comparable hair bundle phenotypes in mice with a disruption of the gene coding for SorCS2, a protein known elsewhere to play pleiotropic roles in endosomal trafficking and neurotrophic signalling. The mis-localisation of the polarity complex in this model suggested SorCS2 may regulate the subcellular distribution of elements essential for normal hair cell differentiation. Following the embryonic period we observed a persistent up-regulation of SorCS2 expression in cochlear supporting cells, possibly consistent with it acting as a neurotrophin co-receptor.

In our proposed study using the inner ears of mice and chicks, we would use antibody labelling and live imaging to determine whether SorCS2 contributes to the hair cell protein sorting pathway. Morphological and functional analysis, of (1) novel conditional knockout (cKO) mouse models and (2) chick embryos with induced changes of gene expression, would determine the contribution of SorCS2 to inner ear development. We will also use the cKO mice to examine the relationship between SorCS2 and neurotrophin receptors in the mouse organ of Corti, and to assess their combined contribution to the morphological development and survival of supporting cells. Together, these studies will decipher signalling pathways that determine planar polarity and cellular development in a number of tissues within the nervous system.

Planned Impact

Impact Summary

Beneficiaries: Pharmaceutical industry and device manufacturers; Clinicians and audiologists; Deafness charities & patient groups; PDRA and project students.

How they will benefit:
Pharmaceutical industry and device manufacturers (medium to long term impact)
The identification of mechanisms involved in the differentiation and survival of hair cells and supporting cells would provide novel therapeutic targets for the drug industry. With an ageing population with a growing hearing loss problem, it is increasingly evident that big pharma is very keen to move into such growth areas.

Clinicians and audiologists (immediate to medium term impact)
Dissemination of information on the molecular basis of hair bundle morphogenesis will raise awareness of potential new deafness genes, or previously unrecognised mechanisms that are implicated in neurological disorders, and are suspected to have a basis in developmental errors. Previous Grand Round communications from our lab at the Royal National Throat Nose and Ear Hospital have led to new research collaborations with surgeons and audiological physicians.

Deafness charities & patient groups (medium term impact)
Dissemination of information about the basis of mechanosensation by hair cells will help educate charity representatives, major donors and families in the physiology of normal hearing and in the required function of prosthetic devices. Raising awareness on the molecular basis of hearing loss and balance defects to patients and carers will aid them in understanding the complex biology underlying such conditions. Our work with charities such as Action on Hearing Loss, have contributed to fundraising from major donors, and to public communication projects at the science/art interface.

PDRA and project students (short to medium term impact)
The study would have an immediate impact on the PDRA supported by the grant. She would have opportunities to enhance her existing skill-set, particularly in the area of chick developmental biology and the use of novel techniques for transgene induction. This period of research would enhance her Fellowship ambitions in the future, and cement her future in academic research. Our ongoing cell biology research funded by the BBSRC has spawned several new projects which have been taken on by Masters students (Brain Sciences, and Audiology), and has led to a successful application for a PhD Studentship on the potential impact of glial cell biology on tinnitus (funded recently by Action on Hearing Loss). We foresee comparable offshoot projects from the plan of work outlined here, and this may lead to the future recruitment of talented individuals to the fields of auditory cell biology and sensory neuroscience.


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