<i>Gbx2</i>is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling

Lin, Zhengshi; Cantos, Raquel; Patente, Maria; Wu, Doris K.

doi:10.1242/dev.01804

Cited by 85 publications

(122 citation statements)

References 55 publications

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“…Although initially uniform, expression of sp8 becomes restricted to the dorsal region of the OV, which will give rise to SCC and ED. Loss of sp8 resulted in otic dysmorphogenesis, similar to mouse mutants of fgf3, mafb, and gbx2 (28,38,39): absence of ED, abnormal SCC, swelling of the membranous labyrinth, abnormal sensory organs, accompanied by epithelial dilation (Fig. 5), the most common phenotypes of endolymphatic hydrops.…”

Section: Discussionmentioning

confidence: 65%

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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: Discussionmentioning

confidence: 65%

“…4 A-D). As in mice (28), mafb is expressed in r5 and r6 in X. tropicalis embryos. In TALENor MO-injected embryos, the mafb expression domain was elongated laterally and especially expanded in the future otic territory (Fig.…”

Section: Resultsmentioning

confidence: 89%

Sp8 regulates inner ear development

Chung

Medina-Ruiz

Harland

2014

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

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“…−/− embryos show variable vestibular malformations that are generally milder than those seen in Wnt1/3a mutants (Lin et al 2005). This raises the possibility that the inner ear defects in Wnt1…”

Section: Wnt Regulates Otic Development Genes and Development 1619mentioning

confidence: 99%

“…All that remained was a truncated cochlear-like structure. The absence of vestibular development in Wnt1 −/− ; Wnt3a −/− embryos is likely due to the down-regulation of Dlx5/6 and Gbx2 within the otic vesicle since overlapping phenotypes are apparent in embryos carrying mutations in these genes (Robledo et al 2002;Lin et al 2005).…”

Section: Wnt3amentioning

confidence: 99%

Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh

Riccomagno¹,

Takada²,

Epstein³

2005

Genes Dev.

230

321

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The inner ear is partitioned along its dorsal/ventral axis into vestibular and auditory organs, respectively. Gene expression studies suggest that this subdivision occurs within the otic vesicle, the tissue from which all inner ear structures are derived. While the specification of ventral otic fates is dependent on Shh secreted from the notochord, the nature of the signal responsible for dorsal otic development has not been described. In this study, we demonstrate that Wnt signaling is active in dorsal regions of the otic vesicle, where it functions to regulate the expression of genes (Dlx5/6 and Gbx2) necessary for vestibular morphogenesis. We further show that the source of Wnt impacting on dorsal otic development emanates from the dorsal hindbrain, and identify Wnt1 and Wnt3a as the specific ligands required for this function. The restriction of Wnt target genes to the dorsal otocyst is also influenced by Shh. Thus, a balance between Wnt and Shh signaling activities is key in distinguishing between vestibular and auditory cell types.

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“…Upon Gbx2 inactivation, r1-r3 fail to become defined (Wassarman et al, 1997;Li et al, 2002Li et al, , 2005. Furthermore, r4-r6 develop, but exhibit gene expression defects (Lin et al, 2005). More recent studies using Gbx2 neo hypomorphic embryos, in which Gbx2 levels are 6-10% of normal, have shown a more stringent requirement for Gbx2 function in the development of r2 and its derivatives, including nV, than either r1 or r3 (Waters and Lewandoski, 2006).…”

Section: Introductionmentioning

confidence: 99%

Evolutionarily conserved function of Gbx2 in anterior hindbrain development

et al. 2011

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The amino acid sequence across the DNA-binding homeodomain of Gbx2 is highly conserved across multiple species. In mice, Gbx2 is essential for establishment of the midbrain-hindbrain boundary (MHB), and in development of anterior hindbrain structures, rhombomeres (r) 1-r3, and the r2/r3-derived cranial nerve V. In contrast, studies in zebrafish have implicated gbx1 in establishment of the MHB. Therefore, we tested potential roles for gbx2 in anterior hindbrain development in zebrafish. gbx2 knockdown with antisense morpholino results in increased cell death in r2, r3, and r5 and a truncation of the anterior hindbrain, similar to the defect in Gbx2 2/2 mice. Moreover, there is abnormal clustering of cranial nerve V cell bodies in r2 and r3 indicative of defects in aspects of anterior hindbrain patterning. These phenotypes can be rescued by expression of the mouse GBX2 protein. These results suggest that gbx2/Gbx2 has an evolutionarily conserved role in anterior hindbrain development. Developmental Dynamics 240:828-838,

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Gbx2is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling

Cited by 85 publications

References 55 publications

Sp8 regulates inner ear development

Sp8 regulates inner ear development

Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh

Evolutionarily conserved function of Gbx2 in anterior hindbrain development

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