Sussex Neuroscience

Professor Guy Richardson FRS

Professor Guy Richardson, FRS

Guy

Molecular and Cellular Basis of Hearing and Deafness

Our senses of hearing and balance depend upon the hair cells of the inner ear and the extracellular matrices with which the hair bundles of these cells interact. The extracellular matrices present in different sensory organs of the inner ear differ in their structure and composition, with the cupulae of the semi-circular canal organs being the simplest and the tectorial membrane of the cochlea being the most complex. These matrices contain glycoproteins like otogelin and Tecta, proteins that are only expressed at high levels in the inner ear. The tectorial membrane additionally contains fibrillar collagens, proteins that are also expressed in abundance elsewhere in the body. Fibrillar collagens are only found in the tectorial membranes of higher vertebrates, are precisely organised in parallel bundles across the radial axis of the membrane, and are thought to be a specialisation that allows hearing to occur over an extended range of frequencies. Mutations in genes encoding both the collagenous and non-collagenous proteins of the tectorial membrane cause hereditary deafness, and missense mutations in Tecta are one of the more common causes of autosomal, dominant, non-syndromic hearing loss in humans, causing either early onset or progressive, later onset forms of deafness.

Quite how the tectorial membrane forms during development and how different mutations cause morphologically distinct changes in its structure remain to be understood. The nine or more proteins that form the membrane are secreted into an extracellular compartment and self assemble on the apical surface of the cochlear epithelium into a structure that is highly organised and precisely graded in its dimensions along the length of the cochlea. The project aims to discover how this happens and will employ a variety of technical approaches. These will include (i) confocal and electron microscopic analysis of tectorial membrane development in wild type mice and those with null mutations in one or more of the non-collagenous tectorial membrane proteins, (ii) long-term live imaging of collagen fibril distribution in the tectorial membranes of cochleae that are developing in vitro, (iii) an analysis of tectorial membrane development in mice with mutations in genes that affect planar polarity and convergent extension in the cochlea, (iv) the application of directed forces to the developing cochlear epithelium, and (v) the transgenic over-expression of collagens in the otoconial membranes of the saccule and utricle, polarised sensory epithelia in which collagen is not a normal constituent of the overlying extracellular matrix. 

The project would suit a candidate with an interest in the development of neurosensory organs and cell biology.

Selected publications

(For full list of publications and more details about the lab, please visit: http://www.sussex.ac.uk/lifesci/richardsonlab/)

Legan PK, Goodyear RJ, Morín M, Mencia A, Pollard H, Olavarrieta L, Korchagina J, Modamio-Hoybjor S, Mayo F, Moreno F, Moreno-Pelayo MA, Richardson GP (2014) Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane. Hum Mol Genet 23:2551-2568.

Sellon JB, Ghaffari R, Farrahi S, Richardson GP, Freeman DM (2014) Porosity controls spread of excitation in tectorial membrane traveling waves.
Biophys J 106:1406-13.

Cheatham MA, Goodyear RJ, Homma K, Legan PK, Korchagina J, Naskar S, Siegel J, Dallos P, Zheng J, Richardson GP (2014) Loss of the tectorial membrane protein, Ceacam16, enhances spontaneous, stimulus frequency and transiently-evoked otoacoustic emissions. J Neurosci 34(31):10325-38.