Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene

Wnt signaling has been implicated in the control of cell proliferation and in synapse formation during neural development, and these actions are presu med to be mediated by frizzled receptors. In this paper we report the pheno type of mice carrying a targeted deletion of the frizzled-4 (fz4) gene. fz4 (-/-) mice exhibit three distinct defects: (1) progressive cerebellar degen eration associated with severe ataxia, (2) absence of a skeletal muscle she ath around the lower esophagus associated with progressive esophageal diste nsion and dysfunction, and (3) progressive deafness caused by a defect in t he peripheral auditory system unaccompanied by loss of hair cells or other auditory neurons. As assayed using a lacZ knock-in reporter, fz4 is widely expressed within the CNS. In particular, fz4 is expressed in cerebellar Pur kinje cells, esophageal skeletal muscle, and cochlear inner hair cells, and the absence of Fz4 in these cells is presumed to account for the fz4(-/-) phenotype. In contrast to the early cell proliferation and patterning effec ts classically ascribed to Wnts, the auditory and cerebellar phenotypes of fz4(-/-) mice implicate Frizzled signaling in maintaining the viability and integrity of the nervous system in later life.