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Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Adaptor protein-3 complex is required for Vangl2 trafficking and planar cell polarity of the inner ear.
Molecular Biology of the Cell 2019 August 16
Planar cell polarity (PCP) regulates coordinated cellular polarity among neighboring cells to establish a polarity axis parallel to the plane of the tissue. Disruption in PCP results in a range of developmental anomalies and diseases. A key feature of PCP is the polarized and asymmetric localization of several membrane PCP proteins, which is essential to establish the polarity axis to orient cells coordinately. However, the machinery that regulates the asymmetric partition of PCP proteins remains largely unknown. In the present study, we show Van gogh-like 2 (Vangl2) in early and recycling endosomes as made evident by colocalization with diverse endosomal Rab proteins. Vangl2 biochemically interacts with adaptor protein-3 complex (AP-3). Using short hairpin RNA knockdown, we found that Vangl2 subcellular localization was modified in AP-3-depleted cells. Moreover, Vangl2 membrane localization within the cochlea is greatly reduced in AP-3-deficient mocha mice, which exhibit profound hearing loss. In inner ears from AP-3-deficient mocha mice, we observed PCP-dependent phenotypes, such as misorientation and deformation of hair cell stereociliary bundles and disorganization of hair cells characteristic of defects in convergent extension that is driven by PCP. These findings demonstrate a novel role of AP-3-mediated sorting mechanisms in regulating PCP proteins.
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