Related Experiment Video
Updated: Aug 9, 2026
Investigating Protein-protein Interactions in Live Cells Using Bioluminescence Resonance Energy Transfer
Published on: May 26, 2014
Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene
1Department of Molecular Biology and Genetics, Division of Comparative Medicine, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
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 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.
Insights
Mice lacking the frizzled-4 (Fz4) gene show progressive cerebellar degeneration, esophageal dysfunction, and deafness. This suggests Frizzled signaling is crucial for maintaining nervous system integrity in adult animals.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Wnt signaling pathways, mediated by frizzled receptors, are known to influence neural development.
- Frizzled-4 (Fz4) is a specific receptor within this pathway, but its precise role in later life is less understood.
Purpose of the Study:
- To investigate the in vivo function of the frizzled-4 (Fz4) gene.
- To characterize the physiological consequences of Fz4 gene deletion in mice.
Main Methods:
- Generation and analysis of frizzled-4 knockout (fz4-/-) mice.
- Phenotypic characterization including neurological, esophageal, and auditory assessments.
- Utilizing a lacZ knock-in reporter to map Fz4 expression patterns in the central nervous system (CNS) and peripheral tissues.
Main Results:
- fz4-/- mice displayed progressive cerebellar degeneration and ataxia.
- Absence of a skeletal muscle sheath in the lower esophagus led to distension and dysfunction.
- Peripheral auditory defects causing progressive deafness were observed without hair cell or neuron loss.
Conclusions:
- Frizzled-4 (Fz4) plays a critical role in maintaining the structural integrity and function of the cerebellum and peripheral auditory system.
- The findings indicate Frizzled signaling is essential for the long-term viability and maintenance of the nervous system, extending beyond early developmental roles.
- Fz4 expression in Purkinje cells, esophageal muscle, and cochlear hair cells correlates with the observed phenotypic defects.
More Related Videos
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
11:10Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Related Concept Videos
01:33Pleiotropy
01:23Cystic Fibrosis: Pathogenesis
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation, but...