The development of semicircular canals in the inner ear: Role of FGFs in sensory cristae

National Institute on Deafness and Other Communication Disorders, Rockville, MD 20850, USA.
Development (Impact Factor: 6.46). 10/2004; 131(17):4201-11. DOI: 10.1242/dev.01292
Source: PubMed


In the vertebrate inner ear, the ability to detect angular head movements lies in the three semicircular canals and their sensory tissues, the cristae. The molecular mechanisms underlying the formation of the three canals are largely unknown. Malformations of this vestibular apparatus found in zebrafish and mice usually involve both canals and cristae. Although there are examples of mutants with only defective canals, few mutants have normal canals without some prior sensory tissue specification, suggesting that the sensory tissues, cristae, might induce the formation of their non-sensory components, the semicircular canals. We fate-mapped the vertical canal pouch in chicken that gives rise to the anterior and posterior canals, using a fluorescent, lipophilic dye (DiI), and identified a canal genesis zone adjacent to each prospective crista that corresponds to the Bone morphogenetic protein 2 (Bmp2)-positive domain in the canal pouch. Using retroviruses or beads to increase Fibroblast Growth Factors (FGFs) for gain-of-function and beads soaked with the FGF inhibitor SU5402 for loss-of-function experiments, we show that FGFs in the crista promote canal development by upregulating Bmp2. We postulate that FGFs in the cristae induce a canal genesis zone by inducing/upregulating Bmp2 expression. Ectopic FGF treatments convert some of the cells in the canal pouch from the prospective common crus to a canal-like fate. Thus, we provide the first molecular evidence whereby sensory organs direct the development of the associated non-sensory components, the semicircular canals, in vertebrate inner ears.

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Available from: Donna M Fekete, Jan 18, 2016
    • "Studies in the zebrafish, chick and mouse have begun to address the mechanisms underlying semicircular canal morphogenesis. It has been proposed that the cristae induce the ducts; signalling molecules, including Fgfs and Bmps, are likely to be involved (Cantos et al., 2000; Chang et al., 2004; Chang et al., 2008; Shawi and Serluca, 2008). Specification of canal tissue also requires the activities of various transcription factor genes, including dlx5, hmx2/3, lmo4, otx1 and sox10 (Hadrys et al., 1998; Acampora et al., 1999; Morsli et al., 1999; Fritzsch et al., 2001; Wang et al., 2001; Merlo et al., 2002; Wang et al., 2004; Lin et al., 2005; Hammond and Whitfield, 2006; Dutton et al., 2009; Deng et al., 2010). "
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    ABSTRACT: Morphogenesis of the semicircular canal ducts in the vertebrate inner ear is a dramatic example of epithelial remodelling in the embryo, and failure of normal canal development results in vestibular dysfunction. In zebrafish and Xenopus, semicircular canal ducts develop when projections of epithelium, driven by extracellular matrix production, push into the otic vesicle and fuse to form pillars. We show that in the zebrafish, extracellular matrix gene expression is high during projection outgrowth and then rapidly downregulated after fusion. Enzymatic disruption of hyaluronan in the projections leads to their collapse and a failure to form pillars: as a result, the ears swell. We have cloned a zebrafish mutant, lauscher (lau), identified by its swollen ear phenotype. The primary defect in the ear is abnormal projection outgrowth and a failure of fusion to form the semicircular canal pillars. Otic expression of extracellular matrix components is highly disrupted: several genes fail to become downregulated and remain expressed at abnormally high levels into late larval stages. The lau mutations disrupt gpr126, an adhesion class G protein-coupled receptor gene. Expression of gpr126 is similar to that of sox10, an ear and neural crest marker, and is partially dependent on sox10 activity. Fusion of canal projections and downregulation of otic versican expression in a hypomorphic lau allele can be restored by cAMP agonists. We propose that Gpr126 acts through a cAMP-mediated pathway to control the outgrowth and adhesion of canal projections in the zebrafish ear via the regulation of extracellular matrix gene expression.
    No preview · Article · Sep 2013 · Development
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    • "Early in auditory system development, the otic placode undergoes invagination to form otocysts, which generate a complex membranous labyrinth and ganglia through a series of morphological events via harmonized coordination of various signaling molecules such as fibroblast growth factors, Notch, bone morphogenetic proteins, and Wnt [1], [2], [3], [4], [5]. To form the cochleovestibular ganglion (CVG) complex, neuroblasts delaminate from otic epithelium into the adjacent mesoderm between embryonic day (E)9.5 and E11.5 [6], [7]. "
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    ABSTRACT: All cellular phenomena and developmental events, including inner ear development, are modulated through harmonized signaling networks. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a major signaling component involved in cross talk with key regulators of development; i.e., Wnt, Notch, and bone morphogenetic proteins. Although Pten function has been studied in various systems, its role in inner ear development is poorly understood. Here, we used inner ear-specific Pten conditional knockout mice and examined the characteristics of the inner ear. In a detailed analysis of the phenotype, reduced cochlear turning and widened epithelia were observed. Phalloidin staining of sensory epithelium revealed that hair cell patterns were disturbed; i.e., additional rows of hair cells were discovered. The neural abnormality revealed a reduction in and disorganization of nerve fibers, including apoptosis at the neural precursor stage. Pten deficiency induced increased phosphorylation of Akt at Ser473. The elevation of inhibitory glycogen synthase kinase 3β Ser9 phosphorylation (pGSK3β) was sustained until the neuronal differentiation stage at embryonic day 14.5, instead of pGSK3β downregulation. This is the first report on the influence of Pten/Akt/GSK3β signaling on the development of spiral ganglia. These results suggest that Pten is required for the maintenance of neuroblast number, neural precursors, and differentiation in the inner ear.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "In the chick as in the mouse, FGFs are also involved in the normal formation of semicircular canals. Ectopic FGF3 and FGF10 expression leads to canal dysmorphogenesis in the chick (Chang et al., 2004), whereas Fgf10 loss in the mouse leads to loss of the posterior canal (Pauley et al., 2003). Earlier experiments have shown that FGF2 is also able to influence neuronal development of the inner ear. "
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    ABSTRACT: The analysis of Fgf10 mouse mutants has demonstrated a critical role for this ligand in neurosensory development of the vertebrate inner ear, and we have been looking to define the direct upstream regulators of Fgf10 in this sensory organ, as part of constructing the programme of early inner ear development. Through the analysis of reporter constructs in transgenic mouse embryos and neonatal mice, in this report we define a minimal 1400bp enhancer from the 5' flanking region of Fgf10. This enhancer drives reporter transgene expression in a manner that recapitulates endogenous expression of Fgf10, from its initial onset in the invaginating otic placode and onwards throughout gestation, controlling Fgf10 expression in all developing sensory patches and in the developing VIIIth ganglion. This regulatory region includes three putative Gata3 binding sites that we demonstrate directly interacts with Gata3 protein through the DNA binding domain with differing affinities. Site directed mutagenesis of all three sites and functional testing in transgenic embryos using reporter transgenes reveals an absolute requirement for Gata3 in controlling Fgf10 expression. Transgenic analysis of individual Gata3 binding site mutations illustrates that only one of these binding site is necessary for reporter expression. Together these data demonstrate that Gata3 directly activates Fgf10 in the early inner ear, and does so through a single binding site.
    Full-text · Article · Dec 2012 · Developmental Biology
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