Apoptosis during inner ear development in human and mouse embryos: an analysis by computer-assisted three-dimensional reconstruction

Nishikori, Tetsuya; Hatta, Toshihisa; Kawauchi, Hideyuki; Otani, Hiroki

doi:10.1007/s004290050255

Cited by 54 publications

(43 citation statements)

References 29 publications

(19 reference statements)

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“…Apoptosis was detected using an antibody to activated Caspase 3, while cell proliferation was detected using an antibody to the M-phase marker phospho-Histone H3. At this stage, Brn4− embryos (n=4) exhibited regional apoptosis in the lateral wall of the basal cochlea, similar to what has been reported in WT embryos (Lang et al 2000;Nishikori et al 1999) (Fig. 5A).…”

Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micesupporting

confidence: 85%

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Braunstein

Crenshaw

Morrow

et al. 2008

JARO

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The T-box transcription factor TBX1 has been identified as the major gene responsible for the etiology of velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutations in POU3F4/BRN4, a POU domain transcription factor, cause DFN3, an X-linked nonsyndromic form of deafness characterized by mixed conductive and sensorineural hearing loss. Inactivation of the murine orthologues of these genes causes similar defects to those seen in humans and has provided excellent models for the study of inner ear development. Tbx1 and Brn4 are expressed in the mesenchymal cells surrounding the otic vesicle and have been shown to play roles in cochlear outgrowth. Furthermore, expression of Brn4 is reduced in Tbx1 null mutants, suggesting a possible genetic interaction between these genes. To test whether Tbx1 and Brn4 function in a common pathway, mice mutant for both genes were generated and analyzed for inner ear defects. Brn4−;Tbx1+/− mutants displayed a significant reduction in the number of turns of the cochlea compared to Brn4− or Tbx1+/− mice. In addition, Brn4−;Tbx1+/− mice displayed structural defects in the apical cochlea indicative of Mondini dysplasia found in patients with either VCFS/DGS or DFN3. These data establish a genetic interaction between Tbx1 and Brn4 relevant to human disease and indicate a function of these genes in signaling from the periotic mesenchyme to the otic vesicle to direct proper coiling of the cochlear duct.

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Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micesupporting

confidence: 85%

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Braunstein

Crenshaw

Morrow

et al. 2008

JARO

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“…In chicken embryos, apoptosis has also been detected in the fusion plates of the semicircular ducts (Fekete et al, 1997). Apoptosis at the fusion plates has not been detected in mouse or human embryos (Martin and Swanson, 1993;Nishikori et al, 1999).…”

Section: Introductionmentioning

confidence: 94%

Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth

et al. 2004

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During inner ear development programmed cell death occurs in specific areas of the otic epithelium but the significance of it and the molecules involved have remained unclear. We undertook an analysis of mouse mutants in which genes encoding apoptosis-associated molecules have been inactivated. Disruption of the Apaf1 gene led to a dramatic decrease in apoptosis in the inner ear epithelium, severe morphogenetic defects and a significant size reduction of the membranous labyrinth, demonstrating that an Apaf1-dependent apoptotic pathway is necessary for normal inner ear development. This pathway most probably operates through the apoptosome complex because caspase 9 mutant mice suffered similar defects. Inactivation of the Bcl2-like (Bcl2l) gene led to an overall increase in the number of cells undergoing apoptosis but did not cause any major morphogenetic defects. In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development. In Apaf1-/-/Bcl2l-/- double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-XL in the otic epithelium is Apaf1-dependent. Furthermore, the otic vesicle failed to close completely in all double mutant embryos analyzed. These results indicate important roles for both Apaf1 and Bcl2l in inner ear development

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“…Cell death has been associated with the resorption of fusion plate cells in the chick vestibulum, but has not been clearly demonstrated in the mouse (Martin and Swanson, 1993;Fekete et al, 1997;Nishikori et al, 1999). A decrease in apoptotic cell death could explain the persistence in fusion plate epithelium in cβcat mutants.…”

Section: Resorption Defects Are Not Due To Alterations In Proliferatimentioning

confidence: 99%

Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation

Rakowiecki

Epstein

2013

Development

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SUMMARYThe morphogenetic program that shapes the three semicircular canals (SSCs) must be executed with extreme precision to satisfy their complex vestibular function. The SSCs emerge from epithelial outgrowths of the dorsal otocyst, the central regions of which fuse and resorb to leave three fluid-filled canals. The Wnt/β-catenin signaling pathway is active at multiple stages of otic development, including during vestibular morphogenesis. How Wnt/β-catenin functionally integrates with other signaling pathways to sculpt the SSCs and their sensory patches is unknown. We used a genetic strategy to spatiotemporally modulate canonical Wnt signaling activity during SSC development in mice. Our findings demonstrate that Wnt/β-catenin signaling functions in a multifaceted manner during SSC formation. In the early phase, Wnt/β-catenin signaling is required to preserve the epithelial integrity of the vertical canal pouch perimeter (presumptive anterior and posterior SSCs) by establishing a sensory-dependent signaling relay that maintains expression of Dlx5 and opposes expression of the fusion plate marker netrin 1. Without this Wnt signaling activity the sensory to non-sensory signaling cascade fails to be activated, resulting in loss of vestibular hair and support cells and the anterior and posterior SSCs. In the later phase, Wnt/β-catenin signaling becomes restricted to the fusion plate where it facilitates the timely resorption of this tissue. Mosaic recombination of β-catenin in small clusters of canal pouch cells prevents their resorption, causing instead the formation of ectopic SSCs. Together, these disparate functions of the Wnt/β-catenin pathway in epithelial maintenance and resorption help regulate the size, shape and number of SSCs.

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Apoptosis during inner ear development in human and mouse embryos: an analysis by computer-assisted three-dimensional reconstruction

Cited by 54 publications

References 29 publications

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth

Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation

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