Lab Overview
We study the development and function of the central nervous system. We are
particularly interested in cell surface receptors such as cadherins and integrins
that mediated cell-cell and cell-extracellular matrix interactions to control
neural stem cell self-renewal, differentiation and migration. We also study
how cell surface receptors such as cadherins control the activity of ion channels.
This is an important part of the mechanism by which sensory cells convert mechanical
into electric signals that can be processed by the nervous system to provide
our sense of hearing and touch.
Highlight
Identification of genes that cause deafness in mice and humans
Martin Schwander
Deafness is the most common form of sensory impairment in the human population
and is frequently caused by recessive mutations. To obtain animal models for
recessive forms of deafness and to identify genes that control the development
and function of the auditory sense organs, we have carried out a forward genetics
screen in mice. We have identified 19 mouse lines with defects in auditory
function. We have mapped several of the affected genetic loci and identified
point mutations in 4 genes. Interestingly, all identified genes are expressed
in mechanosensory hair cells and required for their function. One mutation
maps to a gene that had not been previously linked to deafness. The gene is
a member of small gene family that encodes gasdermin proteins. Gasdermins have
no sequence similarity to any other protein and their function is unknown.
By screening DNA from Iranian pedigrees afflicted with inherited forms of deafness,
we have identified a mutation in the human ortholog of the mouse gene. Using
histology and electrophysiology, we demonstrate that the gasdermin protein
affects the function but not morphology of hair cells. We also show that the
hearing phenotype is progressive in nature, suggesting a potential link between
gasdermins and age related hearing loss. Our findings demonstrate that recessive
screens in mice are powerful tools for identifying genes that control the development
and function of mechanosensory hair cells and cause deafness in humans, as
well as generating animal models for disease.
2006 Publications
Schwander, M., Sczaniecka, A., Grillet, N., Bailey, J.S., Avenarius, M., Najmabadi,
H., Steffy, B.M., Federe, G.C., Lagler, E.A., Banan, R., Hice, R., Grabowski,
L., Keithley, E.M., Ryan, A.F., Housley, G.D., Wiltshire, T., Smith, R.J.H.,
Tarantino, L.M., and Müller, U. (2007). A Forward Genetics Screen in Mice
Identifies Recessive Deafness Traits and Reveals that Pejvakin is Essential
for Outer Hair Cell Function. J. Neurosci, in press.
Belvindrah, R., Hankel, S., Walker, J., Patton, B.L., and Müller, U. (2007).ß1
integrins control the formation of cell chains in the adult rostral migratory
stream. J Neurosi. in press.
Herr, D., Grillet, N., Schwander, M., Rivera, R., Müller, U., and Chun,
J. (2007). Sphingosine 1-phosphate signaling is required for maintenance of
hair cells largely via activation of S12. J. Neurosci, in press.
Huang Z, Shimazu K, Woo NH, Zang K, Muller U, Lu B, Reichardt LF. (2006). Distinct
roles of the ß1-class integrins at the developing and the mature hippocampal
excitatory synapse. J Neurosci 26, 11208-11219.
Belvindrah, R., Nalbant, P. Ding, S., Wu, C. Bokoch, G.M., and Müller,
U. (2006). Integrin-linked kinase regulates Bergmann glial differentiation
during cerebellar development. Mol. Cell. Neurosci. 33, 109-125.
Senften, M., Schwander, M., Kazmierczak, P, Lillo, C., Shin, J.B., Hasson,
T., Geleoc, G.S.G., Gillespie, P.G., Williams, D., Holt, J.R., and Müller,
U. (2006). Physical and functional interaction between protocadherin 15 and
myosin VIIa in mechanosensory hair cells. J. Neurosci. 26, 2060-2071.
