Planar cell polarity (PCP) signaling regulates coordinated polarization of neighboring cells along an axis parallel to the plane of the tissue. Itis required for a multitude of cellular processes, including uniform orientation of hair cells in the organ of Corti of the cochlea and the dynamic convergent extension (CE) process. A number of developmental defects including deafness, neural tube closure defects, and kidney defects are associated with disruption of PCP signaling. It is known that several essential PCP proteins, such as Van gogh-like 2 (Vangl2) and Frizzled (Fz), are localized to cellular membrane in a polarized manner in the cochlea, which is thought to mediate coordination of sensory cell polarity among neighboring cells. However, one outstanding question in the PCP signaling field is how the dynamic CE process is also regulated by the PCP pathway. This is largely due to the lack of understanding of the morphogenesis process of CE and the molecular roles of PCP signaling during the process. In this proposal, we will use the mouse cochlea as the model system and combine mouse genetics, advanced imaging, and molecular and cell biological approached to start addressing key issues in regulation of CE by the PCP pathway.
The specific aims of this proposal are 1) to characterize the cellular polarization process during CE and assess the requirement for PCP signaling in polarized changes in cellular morphology during CE of the cochlea; 2) to determine the cellular role of the PCP protein, Vangl2, in directing morphogenetic polarization during CE. The completion of the specific aims of this proposal will aid in building a complete picture for cellular polarization during convergent extension and define whether the directional information needed to drive polarized cellular intercalation during this process is dependent upon localization of transmembrane PCP proteins. The sponsor (Chen) has made significant advances in the PCP field using the inner ear as a model system to explore the PCP pathway. The proposed study will provide novel insight into the pathway and disease processes influenced by the PCP pathway.
Hearing loss is one of the most common types of sensory loss affecting 1 to 2 in 1,000 newborns. The formation of hearing apparatus requires a set of genes known as planar cell polarity (PCP) genes, and mutations in PCP genes cause defects in the hearing organ. The proposed work will provide novel insight into the molecular and cellular mechanisms that regulate PCP signaling underlying human deafness and potentially identify therapeutic targets for improving hearing.