Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea

Dabdoub, Alain; Donohue, Maura J.; Brennan, Angela; Wolf, Vladimir; Montcouquiol, Mireille; Sassoon, David; Hseih, Jen-Chih; Rubin, Jeffrey S.; Salinas, Patricia C.; Kelley, Matthew W.

doi:10.1242/dev.00448

Cited by 190 publications

(184 citation statements)

References 68 publications

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“…In the mouse inner ear, the alignment of stereociliary bundles on sensory hair cells depends on multiple PCP genes, including Fz6 (17)(18)(19). In the developing inner ear there is a refinement of sensory hair bundle orientation (20,21), consistent with the action of a local consensus rule. In insects, neighboring ridges and bristles generally exhibit a parallel alignment.…”

Section: Discussionmentioning

confidence: 92%

Order from disorder: Self-organization in mammalian hair patterning

Wang

Badea

Nathans

2006

Proc. Natl. Acad. Sci. U.S.A.

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Hairs, feathers, and scales normally exhibit precise orientations with respect to the body axes. In Frizzled6 (Fz6) ؊/؊ mice, the global orientation of hair follicles is disrupted, leading to waves, whorls, and tufts, each comprising many hundreds of hairs. By analyzing the orientation of developing hair follicles, we observed that the nearly parallel arrangement of wild-type (WT) hairs arises from fields of imperfectly aligned follicles, and that the Fz6 ؊/؊ hair patterns arise from fields of grossly misoriented or randomly oriented follicles. Despite their large size, both mutant and WT hair follicles display a remarkable and unexpected plasticity, reorienting on a time scale of days in what seems to be a self-organized refinement process. The essential features of this process can be studied with a simple cellular automata model in which a local consensus ''rule'' acts iteratively to bias each hair's orientation in favor of the average orientation of its neighbors. These experiments define two systems for hair orientation: a global orienting system that acts early in development and is Fz6-dependent, and a local self-organizing system that acts later and is Fz6 independent.frizzled ͉ hair development ͉ planar cell polarity ͉ hair follicle

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Section: Discussionmentioning

confidence: 92%

Order from disorder: Self-organization in mammalian hair patterning

Wang

Badea

Nathans

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Development of this planar polarity is necessary for normal hearing because stereociliary bundles are sensitive to vibrations only in a single plane (21). Planar polarization is also required for convergent extension, a polarized cellular movement that occurs during neural tube closure and cochlear extension.…”

Section: Auditory Neuropathy and Inner Ear Anatomic Defects In Ror1 Mmentioning

confidence: 99%

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Diaz‐Horta

Abad

Sennaroḡlu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicitymatched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.deafness | whole-exome sequencing | inner ear | innervation | NF-κB S ensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Appro...

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“…It also has been established that Dvl functions in the non-canonical Wnt signalling pathway, which regulates polarised reorganisation of the actin cytoskeleton for cell motility in a β-catenin-independent manner [8][9][10] . The importance of the non-canonical Wnt signalling pathway has been established in gastrulation movements, dorsoventral patterning, neuronal migration, cochlear hair cell polarity, cardiogenesis and cancer progression [11][12][13][14][15][16][17][18] .…”

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confidence: 99%

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

et al. 2012

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Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase λ protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.

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Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea

Cited by 190 publications

References 68 publications

Order from disorder: Self-organization in mammalian hair patterning

Order from disorder: Self-organization in mammalian hair patterning

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

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