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

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 have found 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 core PCP signals 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.

 

 

Immunolabeling reveals the positions of hair-bundle components near the cochlear bases of a two-day-old wild-type Daple+/‑mouse (left) and a mutant Daple‑/‑(right) littermate.  Labeling of Gαi (magenta) at the apical cellular surfaces reveals a highly regular pattern in the normal animal; the mutant hair bundles, especially those in the three rows of outer hair cells, are instead oriented in a variety of directions.  Acetylated tubulin, immunolabeled in green, shows that the kinocilia are also misoriented in many bundles.  Phalloidin (gray), which marks the stereocilia, reveals that many hair bundles are distorted, S‑shaped, or even fragmented.

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 sen