Progressive Cerebellar, Auditory, and Esophageal Dysfunction Caused by Targeted Disruption of thefrizzled-4 Gene

Open Access
Publisher Website
Google Scholar
Abstract
Wnt signaling has been implicated in the control of cell proliferation and in synapse formation during neural development, and these actions are presumed to be mediated byfrizzledreceptors. In this paper we report the phenotype of mice carrying a targeted deletion of thefrizzled-4 (fz4) gene.fz4(−/−) mice exhibit three distinct defects: (1) progressive cerebellar degeneration associated with severe ataxia, (2) absence of a skeletal muscle sheath around the lower esophagus associated with progressive esophageal distension and dysfunction, and (3) progressive deafness caused by a defect in the peripheral auditory system unaccompanied by loss of hair cells or other auditory neurons. As assayed using alacZknock-in reporter,fz4 is widely expressed within the CNS. In particular,fz4 is expressed in cerebellar Purkinje cells, esophageal skeletal muscle, and cochlear inner hair cells, and the absence of Fz4 in these cells is presumed to account for thefz4(−/−) phenotype. In contrast to the early cell proliferation and patterning effects classically ascribed to Wnts, the auditory and cerebellar phenotypes offz4(−/−) mice implicate Frizzled signaling in maintaining the viability and integrity of the nervous system in later life.