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Updated: Feb 20, 2026
Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
Published on: February 21, 2016
Identification and characterization of a novel chemically induced allele at the planar cell polarity gene Vangl2
Abdul-Rahman El-Hassan1,2, Vicki Leung3,4, Fares Kharfallah1,5
1CHU Sainte-Justine Research Center, Montréal, QC, Canada.
Abstract:
Planar cell polarity (PCP) signaling controls a number of morphogenetic processes including convergent extension during gastrulation and neural tube formation. Defects in this pathway cause neural tube defects (NTD), the most common malformations of the central nervous system. The Looptail (Lp) mutant mouse was the first mammalian mutant implicating a PCP gene (Vangl2) in the pathogenesis of NTD. We report on a novel chemically induced mutant allele at Vangl2 called Curly Bob that causes a missense mutation p.Ile268Asn (I268N) in the Vangl2 protein. This mutant segregates in a semi-dominant fashion with heterozygote mice displaying a looped tail appearance, bobbing head, and a circling behavior. Homozygote mutant embryos suffer from a severe form of NTD called craniorachischisis, severe PCP defects in the inner hair cells of the cochlea and posterior cristae, and display a distinct defect in retinal axon guidance. This mutant genetically interacts with the Lp allele (Vangl2 S464N ) in neural tube development and inner ear hair cell polarity. The Vangl2I268N protein variant is expressed at very low levels in affected neural and retinal tissues of mutant homozygote embryos. Biochemical studies show that Vangl2I268N exhibits impaired targeting to the plasma membrane and accumulates in the endoplasmic reticulum. The Vangl2I268N variant no longer physically interacts with its PCP partner DVL3 and has a reduced protein half-life. This mutant provides an important model for dissecting the role of Vangl2 in the development of the neural tube, establishment of polarity of sensory cells of the auditory and vestibular systems, and retinal axon guidance.
Insights
A new Vangl2 mutation, Curly Bob (I268N), causes severe neural tube defects and sensory cell polarity issues in mice. This Vangl2 variant impairs protein trafficking and interaction, offering insights into developmental disorders.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
Background:
- Planar cell polarity (PCP) signaling is crucial for embryonic development, including neural tube formation.
- Defects in PCP signaling are linked to neural tube defects (NTDs), common central nervous system malformations.
- The Looptail (Lp) mouse mutant first identified Vangl2's role in NTD pathogenesis.
Purpose of the Study:
- To characterize a novel Vangl2 mutant allele, Curly Bob (Vangl2I268N), and its impact on development.
- To investigate the molecular mechanisms underlying Vangl2I268N function and its role in PCP signaling.
- To establish a new mouse model for studying NTDs and related developmental processes.
Main Methods:
- Generation and phenotypic analysis of a chemically induced Vangl2 mutant mouse (Curly Bob).
- Genetic interaction studies with the existing Looptail (Lp) Vangl2 mutant allele.
- Biochemical analyses of Vangl2I268N protein expression, localization, stability, and interactions.
Main Results:
- The Vangl2I268N mutation causes semi-dominant phenotypes in heterozygotes (looped tail, bobbing head) and severe NTDs (craniorachischisis) in homozygotes.
- Homozygous mutants exhibit profound PCP defects in inner ear hair cells and retinal axon guidance.
- Vangl2I268N protein shows reduced plasma membrane targeting, ER accumulation, impaired DVL3 interaction, and decreased stability.
- The Vangl2I268N allele genetically interacts with the Lp allele in neural tube and inner ear development.
Conclusions:
- The Curly Bob mutant mouse provides a valuable model for studying Vangl2 function in neural tube closure, sensory organ development, and axon guidance.
- Vangl2I268N impairs protein trafficking and interaction, leading to severe developmental defects.
- This study deepens our understanding of PCP signaling pathways in mammalian development and disease.
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