Vestibular dysgenesis in mice lacking Abr and Bcr Cdc42/RacGAPs.

Abstract

The inner ear develops from a simple epithelium (otic placode) into the complex structures specialized for balance (vestibule) and sound (cochlea) detection. Abnormal vestibular and cochlear development is associated with many birth defects. During recent years, considerable progress has been made in understanding the molecular bases of these conditions. To determine the biological function of two closely related GTPase activating proteins for the Cdc42/Rac GTPases, Abr and Bcr, we generated a mouse strain deficient in both of these proteins. Double null mutant mice exhibit hyperactivity, persistent circling, and are unable to swim. These phenotypes are typically found in mice with vestibular defects. Indeed, adult double null mutants display abnormal dysmorphic structures of both the saccule and utricle. Moreover, a total loss of otoconia can be seen in the utricle, whereas in the saccule, otoconia are either missing or their number is drastically decreased and they are abnormally large. Interestingly, both the cochlea and semicircular canals are normal and the double null mutant mice are not deaf. These data demonstrate that Abr and Bcr play important complementary roles during vestibular morphogenesis and that a function of Cdc42/RacGAPs and, therefore, that of the small Rho-related GTPases is critically important for balance and motor coordination.