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Welcome to the Whitfield lab research page.  We are based in the Department of Biomedical Science at the University of Sheffield, and study the development and function of the vertebrate inner ear, using the zebrafish as a model system.

Summary for the non-specialist

The inner ear is the organ that mediates our senses of hearing and balance. It consists of an intricate fluid-filled labyrinth housing a variety of extraordinarily sensitive sensory structures that respond to sound, movement and gravity.

For correct inner ear function it is essential that each of these components  form in exactly the right place in the embryo, as any abnormalities can lead to  deafness or balance disorders.  Indeed, congenital deafness is an important clinical condition, affecting approximately one in every thousand children at birth.

Our aim is to understand how the inner ear develops in the embryo, and the mechanisms that ensure that the different cell types in the ear arise in the correct positions so that they can function accurately.

We use embryos of a small tropical fish, the zebrafish, in our research, as this fish is a superb model for the study of vertebrate inner ear development.

Dissected inner ear from an adult zebrafish.  Image credit: S. S. Yap

Dynamics of inner ear formation.  The movie shows the otic vesicle (developing ear) of a zebrafish embryo on the third day after fertilisation.  Cell membranes are labelled in green, and cell nuclei in red.  Projections of epithelium grow into the centre of the vesicle to form the semicircular canal system.   Movie credit: S. Baxendale and N. van Hateren.  Transgenic lines from Robert Knight and the Nieto lab.

Technical Summary

Current projects in the Whitfield lab include:

Morphogenesis and patterning in the otic placode and vesicle

We are identifying pathways of gene activity that lead to correct axial patterning of the otic epithelium, together with establishment of the neurogenic, sensory and non-sensory domains in the developing ear. We have a long-standing interest in the roles that Hedgehog, Fgf and BMP signalling play in these processes.

Development of the vestibular system

The adult inner ear consists of three interconnected ducts of non-sensory epithelium—the semicircular canals—and various chambers containing sensory hair cells.  We are examining zebrafish lines that develop with morphological defects of the semicircular canal system.  We are using light-sheet microscopy to image semicircular canal formation in these lines, and automated tracking of adult fish to measure any balance deficits.

Image 1

Optical section through a semicircular canal duct (circular structure, top left) and ampulla (sensory chamber) in an adult zebrafish ear.  Inner ear epithelial cells are labelled in green, and actin is stained in red.  The actin-rich hair bundles of the sensory hair cells form a bright red fringe on top of the crista, a band of sensory tissue at the base of the ampulla.  Image credit: S. Baxendale and N. van Hateren.  Transgenic line from Robert Knight.


We are also interested in the formation of the otoliths, biomineralised ‘ear stones’ that sit over patches of sensory hair cells in the ear.  In the zebrafish ear, otoliths are initially tethered to the tips of kinocilia on the sensory hair cells.  Later, they adhere to the sensory patch via the otolithic membrane.  We have recently identified two large glycoproteins involved in zebrafish otolith tethering and adhesion.

Scanning electron micrograph of an asteriscus, the lagenar otolith, from an adult zebrafish inner ear.  Image credit: L. Abbas and C. Hill


Modelling human deafness and vestibular disorders

Some of our zebrafish lines form models for a variety of human diseases, including Waardenburg-Shah syndrome, Branchio-Oto-Renal syndrome and DiGeorge syndrome.

Ototoxicity

A number of drugs used to treat human infections or cancer have ototoxic side effects: they damage sensory hair cells in the ear, leaving a patient with temporary or permanent hearing loss and vestibular impairment.  We are
using the lateral line of the zebrafish embryo as a screening tool to identify compounds that can protect hair cells from the ototoxic effects of drugs such as neomycin and cisplatin.

Sensory neuromasts of the lateral line, labelled with the vital dye DASPEI, in a 5 day old zebrafish larva.