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Daple coordinates organ-wide and cell-intrinsic polarity to pattern inner-ear hair bundles

K. Siletti,Basile Tarchini,A. Hudspeth

Published 2017 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Each hair cell of our auditory and vestibular systems transduces stimuli into electrical signals through its mechanosensitive hair bundle. Because the bundle is responsive along only a single axis, its orientation is crucial. Two systems determine hair-bundle polarity: planar cell polarity proteins, which establish axes along which hair cells are oriented, and the proteins Gαi and LGN. Investigating how these two systems are coordinated so that each hair bundle is appropriately aligned, we identified Daple. In mutants lacking Daple, hair bundles are misoriented and misshapen, a phenotype suggestive of both organ-wide and cell-intrinsic defects. Our study indicates how Daple interacts with proteins of the two systems and proposes a model for its role in determining hair-bundle polarity. The establishment of planar polarization by mammalian cells necessitates the integration of diverse signaling pathways. In the inner ear, at least two systems regulate the planar polarity of sensory hair bundles. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of hair bundles is implemented independently by the G protein complex classically known for orienting the mitotic spindle. Although the primary cilium also participates in each of these pathways, its role and the integration of the two systems are poorly understood. We show that Dishevelled-associating protein with a high frequency of leucine residues (Daple) interacts with PCP and cell-intrinsic signals. Regulated by the cell-intrinsic pathway, Daple is required to maintain the polarized distribution of the core PCP protein Dishevelled and to position the primary cilium at the abneural edge of the apical surface. Our results suggest that the primary cilium or an associated structure influences the domain of cell-intrinsic signals that shape the hair bundle. Daple is therefore essential to orient and pattern sensory hair bundles.

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