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WIREs Dev Biol
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Developmental regulation of planar cell polarity and hair‐bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics

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Hearing loss is the most common and costly sensory defect in humans and genetic causes underlie a significant proportion of affected individuals. In mammals, sound is detected by hair cells (HCs) housed in the cochlea of the inner ear, whose function depends on a highly specialized mechanotransduction organelle, the hair bundle. Understanding the factors that regulate the development and functional maturation of the hair bundle is crucial for understanding the pathophysiology of human deafness. Genetic analysis of deafness genes in animal models, together with complementary forward genetic screens and conditional knock‐out mutations in essential genes, have provided great insights into the molecular machinery underpinning hair‐bundle development and function. In this review, we highlight recent advances in our understanding of hair‐bundle morphogenesis, with an emphasis on the molecular pathways governing hair‐bundle polarity and orientation. We next discuss the proteins and structural elements important for hair‐cell mechanotransduction as well as hair‐bundle cohesion and maintenance. In addition, developmental signals thought to regulate tonotopic features of HCs are introduced. Finally, novel approaches that complement classic genetics for studying the molecular etiology of human deafness are presented. WIREs Dev Biol 2016, 5:85–101. doi: 10.1002/wdev.202 This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Nervous System Development > Vertebrates: Regional Development Birth Defects > Organ Anomalies
Cross‐sectional diagram of the cochlear duct. The scala media, or cochlear duct, is shaded light blue and contains potassium‐enriched endolymph secreted from the stria vascularis. The scala vestibuli and scala tympani, separated from the cochlear duct by Reissner's membrane and the basilar membrane, respectively, are shaded pink and contain the perilymph. Auditory hair cells are colored blue, and supporting cells of the organ of Corti are orange. Efferent nerve fibers innervating inner hair cells are colored blue and afferent nerve fibers innervating all rows are red. Other cells types residing outside the organ of Corti are colored green. IHC, inner hair cell; OHCs, outer hair cells.
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Schematic representation of tonotopic gradients along the basal‐apical axis of the mammalian cochlea. Graded differences in morphological and molecular features underlie regional differences in the mechanical and electrical properties of hair cells.
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A two‐tier model of the establishment of planar cell polarity. Coordinated kinocilium/basal body positioning and hair‐bundle orientation is achieved through the integration of intercellular signaling (blue box) with microtubule‐mediated, hair‐cell intrinsic polarity machinery (green box).
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Mechanisms for asymmetric cell division of Drosophila neuroblasts. Several protein complexes localize to the apical neuroblast cortex during mitosis to regulate asymmetric cell division. INSC links the Baz/Par6/aPKC complex to Pins, which in turn forms a complex with Gαi and Mud, thereby coupling cell polarity with mitotic spindle orientation. Mud engages the cytoplasmic dynein motor to exert force on astral microtubules to orient the spindle.
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Model for establishment of hair‐bundle polarity by microtubule‐mediated hair cell‐intrinsic machinery. Left, en face diagram of an individual hair cell showing the distribution of proteins implicated in basal body positioning, colored according to the key. The nascent hair bundle is colored pink with the basal body (gray circle) at its vertex. Centriolar microtubules are depicted as blue lines. Right, magnified view of the boxed area on the left. During development, cortical LGN/Gαi recruits LIS1/dynein to exert force on centriolar microtubules, pulling the kinocilium/basal body toward the lateral hair cell cortex. Interaction of microtubule plus‐ends with the hair cell cortex stimulates Rac‐PAK signaling, likely through delivery of a kinesin‐II cargo. In turn, localized Rac‐PAK activity stabilizes microtubule cortical attachment to position the basal body appropriately. Plus and minus signs indicate the plus‐end and minus‐end of the microtubule, respectively.
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Development of planar cell polarity in the organ of Corti. (a) En face view of the organ of Corti. Arrow indicates the kinocilium at the hair‐bundle vertex. Acetylated tubulin, green; actin, red. (b) Planar‐polarized arrangement of the basal body and the associated daughter centriole along the medial‐lateral axis (arrow). The basal body is labeled by phospho‐β‐catenin staining (red) and centrioles are labeled by Centrin2‐GFP (green). F‐actin, cyan. (c) Schematic diagram of kinocilium/basal body movements and early apical morphogenesis in the mouse. At E15.5, the centrally placed kinocilium/basal body (green dot with red annulus) migrates to the cell periphery where it closely associates with the cortex. A bare zone (orange) devoid of microvilli (small gray dots) subsequently develops in the vicinity of the kinocilium. As the bare zone expands, the kinocilium/basal body relocalizes to a more central position where it aligns along the medial‐lateral axis with the daughter centriole. Here, the nascent hair bundle forms with the kinocilium positioned at its vertex (large gray dots), abutting the expression domain of bare zone proteins. Daughter centrioles, blue dots.
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Organization of the organ of Corti and hair bundle. (a) En face diagram of the mammalian organ of Corti showing the mosaic pattern of hair cells (shaded white) and supporting cells (shaded gray). The mediolateral and longitudinal axes are indicated. Abbreviations indicate distinct cell types: IHC, inner hair cell row; OHC1‐3, outer hair cell row; DC, Deiters' cell; OPC; outer pillar cell; IPC, inner pillar cell; IPhC, inner phalangeal cell. (b) Cross‐sectional diagram of the hair bundle depicting five distinct populations of stereociliary links colored according to the accompanying key. Stereocilia rootlets are anchored in the cuticular plate (shaded gray). The kinocilium and underlying basal body are on the right. (c) En face scanning electron micrograph of the mouse organ of Corti at E18.5. White triangle indicates the kinocilium of an individual hair cell. (d) Left, an E18.5 hair bundle showing the kinocilium (white triangle) lying at the vertex of the hair bundle. Right, a P5 bundle showing the mature V‐shape and staircase arrangement of the three stereocilia rows in an outer hair cell. Note that the kinocilium has been resorbed.
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Nervous System Development > Vertebrates: Regional Development
Birth Defects > Organ Anomalies