Development and Patterning of the Cochlea: From Convergent Extension to Planar Polarity

Abstract

Within the mammalian cochlea, sensory hair cells and supporting cells are aligned in curvilinear rows that extend along the length of the tonotopic axis. In addition, all of the cells within the epithelium are uniformly polarized across the orthogonal neural-abneural axis. Finally, each hair cell is intrinsically polarized as revealed by the presence of an asymmetrically shaped and apically localized stereociliary bundle. It has been known for some time that many of the developmental processes that regulate these patterning events are mediated, to some extent, by the core planar cell polarity (PCP) pathway. This article will review more recent work demonstrating how components of the PCP pathway interact with cytoskeletal motor proteins to regulate cochlear outgrowth. Finally, a signaling pathway originally identified for its role in asymmetric cell divisions has recently been shown to mediate several aspects of intrinsic hair cell polarity, including kinocilia migration, bundle shape, and elongation.

Figure 1.

Changes in distribution of prosensory cells during cochlear outgrowth. Each drawing represents a region near the midbase of the cochlea. (A) At E14, the epithelium is highly pseudostratified. There is no cellular organization and no morphological differentiation has occurred. (B) At E16, immature hair cells have begun to become organized into rows and stratification has decreased although more than two layers of cells are still present. Note the overall decrease in cell density as a result of cellular migration and extension. (C) By P0, the mature cellular pattern is present with a luminal layer of hair cells resting on a basal layer of supporting cells.

Figure 2.

Effects of different mutations on cell patterning. (A) Surface view of the wild-type organ of Corti (OC), illustrating the normal pattern of hair cells and supporting cells. (B) Disruption of notch signaling, as occurs following deletion of Notch1, leads to an overproduction of hair cells but the mosaic of hair cells and supporting cells is still maintained, most likely as a result of recruitment of supporting cells by hair cells. (C) In contrast, the number of hair cells and supporting cells in the OC from a Nectin3 mutant does not significantly differ from wild type, but hair cells are observed to be in contact, indicating a disruption in cellular patterning.

Figure 3.

Vangl2 regulates stereociliary bundle orientation in the cochlea. (A) Scanning electron micrograph of the organ of Corti from a Vangl2^Lp/Lp mouse at E18.5. Stereociliary bundles show varying degrees of misorientation (indicated by arrowheads, arrows, and boxed cells). (B) Confocal image of the surface of the outer hair cell (OHC) region from the organ of Corti of a P0 mouse. Vangl2 is localized to the junctions between the distal sides of Deiters cells (DCs) and the proximal sides of OHCs. (C) Frequency histograms illustrating the distribution of bundle orientations, based on cell type, in control and Vangl2^Lp/Lp cochleae at E18.5. Note that although bundles in wild-type (WT) animals show a limited distribution centered around the optimal (0°) orientation, in Vangl2^Lp/Lp bundles show varying degrees of misorientation based on location. Scale bars, 10 μm (A); 4 μm (B, left); 0.5 μm (B, right). IHC, Inner hair cell. (Panels A and C from Montcouquiol et al. 2003; reproduced, with permission, from Springer Nature. Panel B from Giese et al. 2012; reproduced, with permission, from the authors.)

Figure 4.

Differences in Gpsm2–Pins/G_αi localization between hair cells, Drosophila neuroblasts, sensory organ precursor (SOP). (A,B) In hair cells, between E15.5 to P0, the migration of the kinocilium toward the lateral/abneural side is instructed by an apical accumulation of Gpsm2/G_αi3/Insc/Dlg, whereas an aPKC/Par6 complex is restricted to the medial/neural side. Of note, Daple expression is restricted to the apicolateral junction (darker orange/brown). (C) In later stages, Gpsm2/G_αi3 accumulates at the tip of the longest stereocilia. (D) In delaminating neuroblasts, the Par-6/Baz–Par-3/aPKC and the Pins/G_αi/Mud or Dlg complexes colocalize at the apical cortex and control the apicobasal orientation of the spindle. Pins/G_αi/Mud or Dlg are recruited to the apical cortex through the presence of Insc. (E) In SOPs, Strabismus (Stbm)-Vang, localizes to the anterior cortex and recruits Pins, where they both work to restrict the Par complex to the posterior cortex, maintaining the spindle orientation parallel to the surface of the epithelium. PCP, planar cell polarity.