Altered Cochlear Fibrocytes in a Mouse Model of DFN3 Nonsyndromic Deafness

Minowa, Osamu; Ikeda, Katsuhisa; Sugitani, Yoshinobu; Oshima, Takeshi; Nakai, Shigeyasu; Katori, Yukio; Suzuki, Masuko; Furukawa, Masayuki; Kawase, Tetsuaki; Zheng, Yulian; Ogura, Masaki; Asada, Yosuke; Watanabe, Ken Ichi; Yamanaka, Hitomi; Gotoh, Shimpei; Nishi-Takeshima, M.; Sugimoto, Tetsuo; Kikuchi, Toshihiko; Takasaka, Tomonori; Noda, Tetsuo

doi:10.1126/science.285.5432.1408

Cited by 196 publications

(161 citation statements)

References 15 publications

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“…The Brn4 null phenotype has been previously described (Minowa et al 1999;Phippard et al 1999). However, our analysis uncovered many additional defects.…”

Section: Fig 1 Defects In Mesenchymal Structures Of Mutant Mice a supporting

confidence: 57%

“…Previous reports of Brn4 null mice revealed alterations in the expression of key proteins in spiral ligament fibrocytes that likely contribute to the hearing loss found in these mutants (Minowa et al 1999;Xia et al 2002). Consistent with this, Brn4−;Tbx1+/− mice in this study were found to have profound hearing loss by auditory brain-stem response testing at 3 months of age (not shown).…”

Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micementioning

confidence: 94%

“…Brn4 is not expressed in the otic vesicle but is expressed throughout the periotic mesenchyme (Phippard et al 1998). Mice null for Brn4 exhibit profound hearing loss due to a reduction in endocochlear potential (Minowa et al 1999). This is caused by defects in spiral ligament fibrocytes, which are involved in the potassium homeostasis of the endolymph.…”

Section: Introductionmentioning

confidence: 99%

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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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“…The Brn4 null phenotype has been previously described (Minowa et al 1999;Phippard et al 1999). However, our analysis uncovered many additional defects.…”

Section: Fig 1 Defects In Mesenchymal Structures Of Mutant Mice a supporting

confidence: 57%

Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micementioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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show abstract

“…On the other hand, selective damage to the lateral wall, in the absence of organ of Corti damage clearly can have important effects on hearing levels. For example, in a mouse model of DFN3, with targeted deletion of the BRN-4 gene, there is normal hair cell and spiral ganglion cell development associated with abnormalities in type I, II, and III fibrocytes (Minowa et al 1999). In these mice, EP is decreased and ABR thresholds are elevated.…”

Section: Dynamics Of Cochlear Damage and Associated Changes In Ep Aftmentioning

confidence: 99%

Lateral Wall Histopathology and Endocochlear Potential in the Noise-Damaged Mouse Cochlea

Hirose

Liberman

2003

JARO - Journal of the Association for Research in Otolaryngolog

240

221

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Noise exposure damages the stria and spiral ligament and may contribute to noise-induced threshold shift by altering the endocochlear potential (EP). The aim of this study was to correlate lateral wall histopathology with changes in EP and ABR thresholds. CBA/CaJ mice were exposed to octave band (8-16 kHz) noise for 2 h at intensities ranging from 94 to 116 dB SPL and evaluated 0 h to 8 weeks postexposure. EP in control mice averaged 86 and 101 mV in apical and basal turns, respectively. The 94 dB exposures caused a 40 dB temporary threshold shift (TTS), and there was with no corresponding change in EP. The 112 and 116 dB exposures caused >60 dB threshold shifts at 24 h, and EP was transiently decreased, e.g., to 21 and 27 mV in apical and basal turns after 116 dB. By 1 week postexposure, EP returned to control values in all exposure groups, although those exposed to 112 or 116 dB showed large permanent threshold shifts (PTS). Cochleas were plastic-embedded and serialsectioned for light microscopic and ultrastructural analysis. Acute changes included degeneration of type II fibrocytes of the spiral ligament and strial edema. The strial swelling peaked at 24 h when significant EP recovery had taken place, suggesting that these changes reflect compensatory volume changes. In the chronic state, massive loss of type II fibrocytes and degeneration of strial intermediate and marginal cells was observed with drastic reduction in membrane surface area. The results suggest that EP shifts do not occur with TTS and also do not add significantly to PTS in the steady state. However, EP loss could contribute to acute threshold shifts that resolve to a PTS. EP recovery despite significant strial degeneration may be partly due to decreased transduction current caused by hair cell damage.

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“…RNA in situ hybridization was performed as described (Minowa et al 1999). Digoxygenin labelled riboprobes were synthesized by using the following murine cDNAs: 1.0-kb Pax1, 290-bp Pax9 (kindly provided by Dr K. Imai, GSF-Research Center for Environment and Health, Neuherberg, Germany), 1.1-kb MFH-1 (kindly provided by Dr N. Miura, Akita University, Akita, Japan), 400-bp Col2a1, 440-bp Col9a2, 360-bp Col11a2, 470-bp aggrecan (kindly provided by DrBenoit de Crombrugghe, University of Texas, MD Anderson Cancer Center, Houston, TX), 300-bp Col10a1 (kindly provided by K. S. E. Cheah, Hong Kong University, Hong Kong, China), 1.2-kb osteopontin (kindly provided by Dr S. Nomura, Osaka University, Osaka, Japan), and 450-bp Hox11 (kindly provided by Dr S. J. Korsmeyer, Harvard Medical School, Boston, MA).…”

Section: Cell Proliferation and Apoptosis Assaysmentioning

confidence: 99%

Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation

et al. 2000

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Altered Cochlear Fibrocytes in a Mouse Model of DFN3 Nonsyndromic Deafness

Cited by 196 publications

References 15 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

Lateral Wall Histopathology and Endocochlear Potential in the Noise-Damaged Mouse Cochlea

Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation

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