Use of Mouse Genetics for Studying Inner Ear Development

Abstract

The analysis of mouse mutants has become an almost indispensable tool in modern biology. The understanding of inner ear development has been facilitated by the use of mice from chemical- and radiation-induced mutagenesis screens, as well as gene-targeting strategies such as knockout models. In particular, our understanding of hereditary gross malformations and neuroepithelial defects that underlie human deafness has been aided by the analysis of comparable gene defects in mice. Mice with mutations in transcription factor genes such as Pax2 and Hmx3 have illustrated the early compartmentalization of the otocyst, whereas defects in endolymph homeostasis, such as those found in Pendred syndrome, show how malformations of the inner ear can arise through fluid changes within it. In addition, a surprisingly large number of mice with hearing and balance problems exhibit defects in sensory hair cell differentiation. From these animals we have been able to identify key gene pathways, such as the Notch signaling pathway, that are involved in cell fate determination and maturation in the inner ear. We have also been able to identify some of the major structural, cytoskeletal components of the mechanotransducing hair cells, such as unconventional myosins and other motor proteins such as prestin. Analysis of mutant mice has been incredibly useful in the identification of functionally, and therefore clinically, important genes and together with recent molecular advances, such as the sequencing of the mouse genome, have taken mouse genetics to a new level that will surely make it indispensable in the future analysis of mammalian development.