Line up and listen: Planar cell polarity regulation in the mammalian inner ear

doi:10.1016/j.semcdb.2009.02.007

Seminars in Cell & Developmental Biology

Volume 20, Issue 8, October 2009, Pages 978-985

https://doi.org/10.1016/j.semcdb.2009.02.007 Get rights and content

Abstract

The inner ear sensory organs possess extraordinary structural features necessary to conduct mechanosensory transduction for hearing and balance. Their structural beauty has fascinated scientists since the dawn of modern science and ensured a rigorous pursuit of the understanding of mechanotransduction. Sensory cells of the inner ear display unique structural features that underlie their mechanosensitivity and resolution, and represent perhaps the most distinctive form of a type of cellular polarity, known as planar cell polarity (PCP). Until recently, however, it was not known how the precise PCP of the inner ear sensory organs was achieved during development. Here, we review the PCP of the inner ear and recent advances in the quest for an understanding of its formation.

Introduction

Fields across which cells are oriented with stunning precision are a recurring theme in biology and have riveted scientists for centuries. To understand the biological mechanism that generates the regular alignment of cuticular hairs and bristles in Drosophila melanogaster, Gubb and Garcia-Bellido exploited the power of fruitfly genetics and identified a small set of genes that constitute conserved components of what is now termed the planar cell polarity (PCP) pathway, which governs the genesis of this reiterative pattern of uniformly oriented structures [1]. Planar cell polarity refers to the coordinated orientation of cells in the two-dimensional plane of a cell sheet. It is now well known that the PCP pathway operates in both invertebrates and vertebrates, orchestrating complex tissue movements and patterning events in different types of tissues during development. During evolution, intrinsic differences in morphogenetic processes between invertebrates and vertebrates and among different types of tissues have led to variations in the ways in which the PCP pathway has been deployed. However, in many systems showing PCP features, PCP signaling functions as a crucial biological switch-board integrating long-range signals with local ones to precisely orient diverse subcellular structures or entire cell populations along a specific axis. Among the finest model systems in which to study the exquisite capacities and detailed mechanics of the PCP signaling pathway in vertebrates are the sensory epithelia of the inner ear. This review will therefore focus on the role of PCP signaling in the development of the fine cellular architecture of the mammalian inner ear—the basis of its extraordinary operational capabilities for hearing and balance.

Section snippets

The inner ear—a marvel in miniature

The mammalian inner ear detects and processes both auditory and positional information over a considerable range with remarkable sensitivity and resolution. It contains precisely organized fields of mechanosensory hair cells, intervening supporting cells and neurons that are functionally arranged in fluid-filled chambers to produce three types of highly specialized sensory epithelia (Fig. 1A): (a) the organ of Corti that detects auditory signals; (b) the maculae of the utricle and the saccule

The vertebrate PCP signaling pathway

The generation of planar polarity in any tissue presents two important challenges: first, to polarize individual cells in the field and second, to ensure that all the cells in the field are aligned along the correct axis and perfectly with respect to each other. Based on data accrued over the last decade from several model systems, it has become amply clear that conceptually, PCP signaling comprises at least three regulatory modules to accomplish coordinated alignment of all the cells in a

Conclusions

The distinct and coordinated cellular polarity in the inner ear sensory organs (Fig. 1) offers an excellent paradigm for cellular and molecular mechanisms in vertebrate PCP signaling. Together with findings from other model systems, the study of inner ear PCP revealed a potentially conserved mechanism operating in the vertebrates to regulate the formation of a reiterative pattern of polarized structures in cells across a tissue field. In particular, several genes conserved from Drosophila,

Acknowledgements

We would like to thank Dr. Dong Qian for providing an image used for Fig. 1, Dongdong Ren for discussions on the cellular architecture of the vestibular epithelia, Michael Kelly and Maria Chacon for assistance with the manuscript. Several inner ear studies cited are supported by NIH research grants to P.C. (RO1 DC005213 and DC007423).

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Rack1 features seven WD40 repeats that fold into a multifaceted scaffold used to build signaling complexes in a context-dependent manner. Previous in vitro studies have revealed associations between Rack1 and many other proteins. Rack 1 is required for establishing planar cell polarity (PCP) in zebrafish and Xenopus. However, any molecular role of Rack1 in protein complexes or polarity regulation remains unclear. Here, we show that Rack1 is an essential gene in mice. Conditional knockout of Rack1 shortened the cochlear duct and induced cellular patterning defects characteristic of defective convergent extension (this PCP process is mediated by cellular junctional remodeling in the developing cochlear epithelium). Also, cochlear hair cells were no longer uniformly oriented in Rack1 conditional knockout mutants. Rack1 was enriched in the cellular cortices of sensory hair cells. In Rack1-deficient cochleae, E-cadherin expression at the cellular boundaries was greatly reduced. Together, the findings reveal a molecular role of Rack1 in PCP signaling that likely involves modulation of E-cadherin levels at the adherens junctions of the plasma membrane.
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The inner ear is one of the most complex structures in the mammalian body. Embedded within it are the hearing and balance sensory organs that contain arrays of hair cells that serve as sensors of sound and acceleration. Within the sensory organs, these hair cells are prototypically arranged in regular mosaic patterns. The development of such complex, yet precise, patterns require the coordination of differentiation, growth, and morphogenesis, both at the tissue and cellular scales. In recent years, there is accumulating evidence that mechanical forces at the tissue, the cellular, and the subcellular scales coordinate the development and organization of this remarkable organ. Here, we review recent works that reveal how such mechanical forces shape the inner ear, control its size, and establish regular cellular patterns. The insights learned from studying how mechanical forces drive the inner ear development are relevant for many other developmental systems in which precise cellular patterns are essential for their function.
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The neural crest—a key innovation of the vertebrates—gives rise to diverse cell types including melanocytes, neurons and glia of the peripheral nervous system, and chondrocytes of the jaw and skull. Proper development of the cephalic region is dependent on the tightly-regulated specification and migration of cranial neural crest cells (NCCs). The core PCP proteins Frizzled and Disheveled have previously been implicated in NCC migration. Here we investigate the functions of the core PCP proteins Prickle1a and Prickle1b in zebrafish cranial NCC development. Using analysis of pk1a and pk1b mutant embryos, we uncover similar roles for both genes in facilitating cranial NCC migration. Disruption of either gene causes pre-migratory NCCs to cluster together at the dorsal aspect of the neural tube, where they adopt aberrant polarity and movement. Critically, in investigating Pk1-deficient cells that fail to migrate ventrolaterally, we have also uncovered roles for pk1a and pk1b in the epithelial-to-mesenchymal transition (EMT) of pre-migratory NCCs that precedes their collective migration to the periphery. Normally, during EMT, pre-migratory NCCs transition from a neuroepithelial to a bleb-based and subsequently, mesenchymal morphology capable of directed migration. When either Pk1a or Pk1b is disrupted, NCCs continue to perform blebbing behaviors characteristic of pre-migratory cells over extended time periods, indicating a block in a key transition during EMT. Although some Pk1-deficient NCCs transition successfully to mesenchymal, migratory morphologies, they fail to separate from neighboring NCCs. Additionally, Pk1b-deficient NCCs show elevated levels of E-Cadherin and reduced levels of N-Cadherin, suggesting that Prickle1 molecules regulate Cadherin levels to ensure the completion of EMT and the commencement of cranial NCC migration. We conclude that Pk1 plays crucial roles in cranial NCCs both during EMT and migration. These roles are dependent on the regulation of E-Cad and N-Cad.
From Planar Cell Polarity to Ciliogenesis and Back: The Curious Tale of the PPE and CPLANE proteins
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Why some genes are more popular than others remains an open question, but one example of this phenomenon involves the genes controlling planar cell polarity (PCP), the polarization of cells within a plane of a tissue. Indeed, the so-called ‘core’ PCP genes such as dishevelled, frizzled, and prickle have been extensively studied both in animal models and by human genetics. By contrast, other genes that influence PCP signaling have received far less attention. Among the latter are inturned, fuzzy, and fritz, but recent work should bring these once obscure regulators into the limelight. We provide here a brief history of planar polarity effector (PPE) and CPLANE (ciliogenesis and planar polarity effector) proteins, discuss recent advances in understanding their molecular mechanisms of action, and describe their roles in human disease.
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We will, however, focus only on Wnt/β-catenin, hereafter referred to as Wnt signalling, since there is no evidence of interaction between the Wnt/PCP and Notch signalling pathways during the development of the inner ear. For more information on Wnt/PCP in the developing cochlea, see May-Simera and Kelley (2012), Ezan and Montcouquiol (2013), and Rida and Chen (2009). The inner ear originates from a layer of cranial ectoderm localised on either side of the hindbrain.
The Wnt and Notch signalling pathways control proliferation, specification, and cell fate choices during embryonic development and in adult life. Hence, there is much interest in both signalling pathways in the context of stem cell biology and tissue regeneration. In the developing ear, the Wnt and Notch signalling pathways specify otic cells and refine the ventral boundary of the otic placode. Since both signalling pathways control events essential for the formation of sensory cells, such as proliferation and hair cell differentiation, these pathways could hold promise for the regeneration of hair cells in adult mammalian cochlea. Indeed, modulating either the Wnt or Notch pathways can trigger the regenerative potential of supporting cells. In the neonatal mouse cochlea, Notch-mediated regeneration of hair cells partially depends on Wnt signalling, which implies an interaction between the pathways. This review presents how the Wnt and Notch signalling pathways regulate the formation of sensory hair cells and how modulating their activity induces regenerative potential in the mammalian cochlea.
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The cochlear convergent extension (CE) is defined as cellular intercalations along the mediolateral axis and extension along the perpendicular longitudinal axis, which is another character of PCP (Jones and Chen, 2008; Qian et al., 2007). This may be mediated by directly regulating cell adhesion (Chacon-Heszele et al., 2012; Rida and Chen, 2009). Expression of certain PCP pathway molecules was also observed during the development of the inner ear in mice (Jones et al., 2008; Wang et al., 2005).
Planar cell polarity (PCP) signaling regulates cochlear extension and coordinates orientation of sensory hair cells in the inner ear. Retroviral-mediated introduction of the Math1 transcription factor leads to the transdifferentiation of some mature supporting cells into hair cells. Testosterone, a gonadal sex steroid hormone, is associated with neuroprotection and regeneration in Central Nervous System (CNS) development. Experiments were performed in vitro using Ad5-EGFP-Math1/Ad5-Math1 in neonatal mouse cochleas. Establishment of ectopic hair-cell like cell(HCLC) polarity in the lesser epithelial ridge (LER) with or without testosterone-3-(O-carboxymethyl) oxime bovine serum albumin (testosterone-BSA) treatment was investigated to determine the role of the PCP pathway in regulating ectopic regenerated (HCLCs) through induction by Math1 and testosterone treatment. After Math1 infection, new ectopic regenerated HCLCs were detected in the LER. After the HCLCs developed actin-rich stereocilia, the basal bodies moved from the center to the distal side. Moreover, the narrower, non-sensory LER region meant that the convergent extension (CE) was also established after transfection with Math1. After 9 days of in vitro testosterone-BSA treatment, more Edu(+), Sox2(+), and HCLC cells were observed in the LER with an accompanying downregulation of E-cadherin. Interestingly, the CE of the Ad5-EGFP-math1 treated LER is altered, but the intrinsic cellular polarity of the HCLCs is not obviously changed. In summary, our results indicate that PCP signaling is involved in the development of ectopic HCLCs and the CE of the ectopic sensory region is altered by testosterone-BSA through downregulation of cell–cell adhesion. Testosterone-BSA and Math1 treatment could promote an increase in HCLCs in the LER through proliferation and transdifferentiation.

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ReviewLine up and listen: Planar cell polarity regulation in the mammalian inner ear

Abstract

Introduction

Section snippets

The inner ear—a marvel in miniature

The vertebrate PCP signaling pathway

Conclusions

Acknowledgements

Dev Biol

Semin Cell Dev Biol

Curr Biol

Dev Cell

Cell

Mech Dev

Dev Biol

Hear Res

Dev Cell

Curr Biol

Cell

Dev Cell

Dev Cell

Dev Cell

A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster

J Embryol Exp Morphol

The function and mechanism of convergent extension during gastrulation of Xenopus laevis

J Embryol Exp Morphol

Dishevelled controls cell polarity during Xenopus gastrulation

Nature

Planar cell polarization: an emerging model points in the right direction

Annu Rev Cell Dev Biol

Planar cell polarity: one or two pathways?

Nat Rev Genet

Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals

J Neurosci

Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway

Nat Genet

The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells

J Neurosci

Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development

PLoS Genetics

Ciliary proteins link basal body polarization to planar cell polarity regulation

Nat Genet

Identification of Vangl2 and Scrb1 as planar polarity genes in mammals

Nature

Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation

Development

PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates

Nature

Review
Line up and listen: Planar cell polarity regulation in the mammalian inner ear