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The Journal of Neuroscience, July 1, 2001, 21(13):4761-4771
Progressive Cerebellar, Auditory, and Esophageal Dysfunction
Caused by Targeted Disruption of the
frizzled-4 Gene
Yanshu
Wang1, 6,
David
Huso2,
Hugh
Cahill3, 4,
David
Ryugo3, 4, and
Jeremy
Nathans1, 4, 5, 6
1 Department of Molecular Biology and Genetics,
2 Division of Comparative Medicine,
3 Department of Otolaryngology-Head and Neck Surgery,
4 Department of Neuroscience, and
5 Department of Ophthalmology, 6 Howard Hughes
Medical Institute, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205
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 by
frizzled receptors. In this paper
we report the phenotype of mice carrying a targeted deletion of the
frizzled-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 a lacZ knock-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 the
fz4(/) phenotype. In contrast to the early cell
proliferation and patterning effects 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.
Key words:
frizzled-4; cerebellar degeneration; Purkinje
cells; Wnt signaling; esophagus; progressive hearing loss
Copyright © 2001 Society for Neuroscience 0270-6474/01/21134761-11$05.00/0
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