Cilia-driven fluid flow as an epigenetic cue for otolith biomineralization on sensory hair cells of the inner ear

Yu, Xiang; Lau, Doreen; Ng, Chee Peng; Roy, Sudipto

doi:10.1242/dev.057752

Cited by 55 publications

(77 citation statements)

References 32 publications

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“…We examined foxj1.2 expression in TALENinjected embryos and uninjected control embryos. Foxj1.2 expression was detected in the presumptive OV, as previously reported in X. tropicalis and zebrafish embryos (29,30), and this expression was reduced on the sp8 TALEN-injected side (Fig. 4 I and J), suggesting sp8 regulates hair cells via foxj1 and the hair cell defects found in sp8-reduced embryos are likely to be primary effects.…”

Section: Resultssupporting

confidence: 81%

Sp8 regulates inner ear development

Chung

Medina-Ruiz

Harland

2014

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

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A forward genetic screen of N-ethyl-N-nitrosourea mutagenized Xenopus tropicalis has identified an inner ear mutant named eclipse (ecl). Mutants developed enlarged otic vesicles and various defects of otoconia development; they also showed abnormal circular and inverted swimming patterns. Positional cloning identified specificity protein 8 (sp8), which was previously found to regulate limb and brain development. Two different loss-of-function approaches using transcription activator-like effector nucleases and morpholino oligonucleotides confirmed that the ecl mutant phenotype is caused by down-regulation of sp8. Depletion of sp8 resulted in otic dysmorphogenesis, such as uncompartmentalized and enlarged otic vesicles, epithelial dilation with abnormal sensory end organs. When overexpressed, sp8 was sufficient to induce ectopic otic vesicles possessing sensory hair cells, neurofilament innervation in a thickened sensory epithelium, and otoconia, all of which are found in the endogenous otic vesicle. We propose that sp8 is an important factor for initiation and elaboration of inner ear development.T he vertebrate inner ear is a sensory organ responsible for balance and sound detection. Dysfunction of the inner ear is among the most common congenital disorders, affecting at least 1 in 500 births (1) and ∼40% of sensorineural deafness is associated with inner ear malformations (2). However, the study of hearing and balance impairment in humans is limited by the inability to follow inner ear development. Vertebrates share similarities in the sequence of developmental events that form the inner ear: the formation of an otic placode from an ectodermal thickening, morphogenesis to form the otocyst, and regional patterning of the otic vesicle (OV), resulting in the 3D membranous labyrinth (3, 4). Multipotent sensory progenitor cells are induced in the ectoderm surrounding the anterior neural plate, a domain termed the preplacodal region (PPR), and six1 has been characterized as marking this panplacodal domain. Signals from hindbrain and the regional expression of different transcription factors differentiate the PPR into the otic placode. The OV is partitioned by asymmetrical expression of various developmental regulators to pattern subdomains of the developing inner ear.The abilities of Xenopus to elucidate the cellular and molecular aspects of developmental processes position it as a valuable model organism (5-7). Earlier studies of lineage analysis and spatiotemporal expression of transcription factors during inner ear development led to construction of an inner ear fate map in Xenopus and this fate map allows us to interpret gene expression patterns within the context of the anatomy (8, 9). In recent years, genetic and genomic approaches have been developed in Xenopus tropicalis (10-13). To advance our understanding of inner ear development, we have screened N-ethyl-N-nitrosourea (ENU) mutagenized X. tropicalis colonies and recovered an inner ear mutant named eclipse (ecl). The ecl mutant perturbs specificity protei...

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Section: Resultssupporting

confidence: 81%

Sp8 regulates inner ear development

Chung

Medina-Ruiz

Harland

2014

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

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“…Our results support some aspects of the most recent models (Wu et al, 2011;Yu et al, 2011), but differ in other important respects (summarised in supplementary material Table S1). We confirm that tether cell kinocilia are immotile and that groups of motile cilia are present nearby at the OV poles.…”

Section: Introductionsupporting

confidence: 85%

“…This view was later revised in an experimental and modelling study of hydrodynamics in the OV, which proposed that the polar cluster contains both immotile tether cilia and nearby motile cilia (Wu et al, 2011). A further study, using high-speed imaging and genetic evidence, supports the original Riley model (Yu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…These organelles are present on the apical surface of most vertebrate cells and are involved in sensory, signalling and mechanical processes (Bisgrove and Yost, 2006;Ishikawa and Marshall, 2011). Every cell of the zebrafish OV epithelium is monociliated (Riley et al, 1997), and many genes involved in ciliogenesis, intraflagellar transport, ciliary movement, stability and function are expressed in the OV (Tsujikawa and Malicki, 2004;Bisgrove et al, 2005;Omori and Malicki, 2006;Pathak et al, 2007;Omori et al, 2008;SullivanBrown et al, 2008;van Rooijen et al, 2008;Yu et al, 2008;Colantonio et al, 2009;Wilkinson et al, 2009;Gao et al, 2010;Glazer et al, 2010;Kang et al, 2010;May-Simera et al, 2010;Becker-Heck et al, 2011;Clément et al, 2011;Pathak et al, 2011;Ravanelli and Klingensmith, 2011;Rothschild et al, 2011;Yu et al, 2011). Sensory hair cells in the ear each bear a specialised cilium known as the kinocilium.…”

Section: Introductionmentioning

confidence: 99%

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The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle

et al. 2012

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SUMMARYOtoliths are biomineralised structures required for the sensation of gravity, linear acceleration and sound in the zebrafish ear. Otolith precursor particles, initially distributed throughout the otic vesicle lumen, become tethered to the tips of hair cell kinocilia (tether cilia) at the otic vesicle poles, forming two otoliths. We have used high-speed video microscopy to investigate the role of cilia and ciliary motility in otolith formation. In wild-type ears, groups of motile cilia are present at the otic vesicle poles, surrounding the immotile tether cilia. A few motile cilia are also found on the medial wall, but most cilia (92-98%) in the otic vesicle are immotile. In mutants with defective cilia (iguana) or ciliary motility (lrrc50), otoliths are frequently ectopic, untethered or fused. Nevertheless, neither cilia nor ciliary motility are absolutely required for otolith tethering: a mutant that lacks cilia completely (MZovl) is still capable of tethering otoliths at the otic vesicle poles. In embryos with attenuated Notch signalling [mindbomb mutant or Su(H) morphant], supernumerary hair cells develop and otolith precursor particles bind to the tips of all kinocilia, or bind directly to the hair cells' apical surface if cilia are absent [MZovl injected with a Su(H)1+2 morpholino]. However, if the first hair cells are missing (atoh1b morphant), otolith formation is severely disrupted and delayed. Our data support a model in which hair cells produce an otolith precursor-binding factor, normally localised to tether cell kinocilia. We also show that embryonic movement plays a minor role in the formation of normal otoliths.

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“…Disruption of proteins that regulate cilia function can result in a broad spectrum of clinical disorders known as ciliopathies (Sharma et al, 2008). In the zebrafish embryo, Kupffer's vesicle, otic vesicles and the pronephric ducts are examples of organs that assemble motile cilia that project into a lumen and generate fluid flow that is necessary for normal development (Essner et al, 2005;Kramer-Zucker et al, 2005;Yu et al, 2011). In ciliated organs, formation and maintenance of cilia requires docking of a basal body to the apical cell surface, vesicle trafficking of ciliary proteins from the Golgi apparatus to the cilium and movement of cargos through the cilia via intraflagellar transport (Ishikawa and Marshall, 2011).…”

Section: Introductionmentioning

confidence: 99%

Lethal giant larvae 2 regulates development of the ciliated organ Kupffer’s vesicle

et al. 2013

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SUMMARYMotile cilia perform crucial functions during embryonic development and throughout adult life. Development of organs containing motile cilia involves regulation of cilia formation (ciliogenesis) and formation of a luminal space (lumenogenesis) in which cilia generate fluid flows. Control of ciliogenesis and lumenogenesis is not yet fully understood, and it remains unclear whether these processes are coupled. In the zebrafish embryo, lethal giant larvae 2 (lgl2) is expressed prominently in ciliated organs. Lgl proteins are involved in establishing cell polarity and have been implicated in vesicle trafficking. Here, we identified a role for Lgl2 in development of ciliated epithelia in Kupffer's vesicle, which directs left-right asymmetry of the embryo; the otic vesicles, which give rise to the inner ear; and the pronephric ducts of the kidney. Using Kupffer's vesicle as a model ciliated organ, we found that depletion of Lgl2 disrupted lumen formation and reduced cilia number and length. Immunofluorescence and time-lapse imaging of Kupffer's vesicle morphogenesis in Lgl2-deficient embryos suggested cell adhesion defects and revealed loss of the adherens junction component E-cadherin at lateral membranes. Genetic interaction experiments indicate that Lgl2 interacts with Rab11a to regulate E-cadherin and mediate lumen formation that is uncoupled from cilia formation. These results uncover new roles and interactions for Lgl2 that are crucial for both lumenogenesis and ciliogenesis and indicate that these processes are genetically separable in zebrafish.

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Cilia-driven fluid flow as an epigenetic cue for otolith biomineralization on sensory hair cells of the inner ear

Cited by 55 publications

References 32 publications

Sp8 regulates inner ear development

Sp8 regulates inner ear development

The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle

Lethal giant larvae 2 regulates development of the ciliated organ Kupffer’s vesicle

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