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Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.

Bosman EA, Quint E, Fuchs H, Hrabé de Angelis M, Steel KP - Dev. Biol. (2009)

Bottom Line: Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion.Lastly we show that Six1 genetically interacts with Jag1.In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

ABSTRACT
Large-scale mouse mutagenesis initiatives have provided new mouse mutants that are useful models of human deafness and vestibular dysfunction. Catweasel is a novel N-ethyl-N-nitrosourea (ENU)-induced mutation. Heterozygous catweasel mutant mice exhibit mild headtossing associated with a posterior crista defect. We mapped the catweasel mutation to a critical region of 13 Mb on chromosome 12 containing the Six1, -4 and -6 genes. We identified a basepair substitution in exon 1 of the Six1 gene that changes a conserved glutamic acid (E) at position 121 to a glycine (G) in the Six1 homeodomain. Cwe/Cwe animals lack Preyer and righting reflexes, display severe headshaking and have severely truncated cochlea and semicircular canals. Cwe/Cwe animals had very few hair cells in the utricle, but their ampullae and cochlea were devoid of any hair cells. Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion. Lastly we show that Six1 genetically interacts with Jag1. We propose that the catweasel phenotype is due to a hypomorphic mutation in Six1 and that catweasel mice are a suitable model for branchio-oto-renal syndrome. In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.

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Mice homozygous for the catweasel have middle and inner ear defects. (A–C) Dissected middle ear ossicles from wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) animals. The long process of the incus was absent in Cwe/Cwe mice (arrowhead). (D–F) Analysis of gross morphology of the inner ear of wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) mice at P21 by glycerol clearing. (G–I) Analysis of gross morphology of the inner ear of wildtype (D), Cwe/+ (E) and Cwe/Cwe (F) embryos at E18.5 by paintfilling. Scale bars: A–C = 500 μm, D–F = 1 mm, G–I = 300 μm; m, malleus; i, incus; lp, long process incus; s, stapes; aa, anterior ampulla; ac, anterior semicircular canal; cc, common crus; co, cochlea; la, lateral ampulla; lc, lateral semicircular canal; pa, posterior ampulla; pc, posterior semicircular canal; sa, saccule.
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fig3: Mice homozygous for the catweasel have middle and inner ear defects. (A–C) Dissected middle ear ossicles from wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) animals. The long process of the incus was absent in Cwe/Cwe mice (arrowhead). (D–F) Analysis of gross morphology of the inner ear of wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) mice at P21 by glycerol clearing. (G–I) Analysis of gross morphology of the inner ear of wildtype (D), Cwe/+ (E) and Cwe/Cwe (F) embryos at E18.5 by paintfilling. Scale bars: A–C = 500 μm, D–F = 1 mm, G–I = 300 μm; m, malleus; i, incus; lp, long process incus; s, stapes; aa, anterior ampulla; ac, anterior semicircular canal; cc, common crus; co, cochlea; la, lateral ampulla; lc, lateral semicircular canal; pa, posterior ampulla; pc, posterior semicircular canal; sa, saccule.

Mentions: We analysed these animals for gross malformations and found that 41% of Cwe/Cwe animals had a unilateral hypoplastic kidney (Table 1; data not shown). Analysis of the middle ear showed that wildtype (n = 2) and Cwe/+ (n = 4) animals had a normal malleus, incus and stapes (Figs. 3A, B). Cwe/Cwe animals (n = 4) had a normal malleus and stapes, but lacked the long process of the incus (Fig. 3C). Analysis of sections through embryos showed that the long process is not present in Cwe/Cwe embryos at E16.5 (data not shown).


Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.

Bosman EA, Quint E, Fuchs H, Hrabé de Angelis M, Steel KP - Dev. Biol. (2009)

Mice homozygous for the catweasel have middle and inner ear defects. (A–C) Dissected middle ear ossicles from wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) animals. The long process of the incus was absent in Cwe/Cwe mice (arrowhead). (D–F) Analysis of gross morphology of the inner ear of wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) mice at P21 by glycerol clearing. (G–I) Analysis of gross morphology of the inner ear of wildtype (D), Cwe/+ (E) and Cwe/Cwe (F) embryos at E18.5 by paintfilling. Scale bars: A–C = 500 μm, D–F = 1 mm, G–I = 300 μm; m, malleus; i, incus; lp, long process incus; s, stapes; aa, anterior ampulla; ac, anterior semicircular canal; cc, common crus; co, cochlea; la, lateral ampulla; lc, lateral semicircular canal; pa, posterior ampulla; pc, posterior semicircular canal; sa, saccule.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2682643&req=5

fig3: Mice homozygous for the catweasel have middle and inner ear defects. (A–C) Dissected middle ear ossicles from wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) animals. The long process of the incus was absent in Cwe/Cwe mice (arrowhead). (D–F) Analysis of gross morphology of the inner ear of wildtype (A), Cwe/+ (B) and Cwe/Cwe (C) mice at P21 by glycerol clearing. (G–I) Analysis of gross morphology of the inner ear of wildtype (D), Cwe/+ (E) and Cwe/Cwe (F) embryos at E18.5 by paintfilling. Scale bars: A–C = 500 μm, D–F = 1 mm, G–I = 300 μm; m, malleus; i, incus; lp, long process incus; s, stapes; aa, anterior ampulla; ac, anterior semicircular canal; cc, common crus; co, cochlea; la, lateral ampulla; lc, lateral semicircular canal; pa, posterior ampulla; pc, posterior semicircular canal; sa, saccule.
Mentions: We analysed these animals for gross malformations and found that 41% of Cwe/Cwe animals had a unilateral hypoplastic kidney (Table 1; data not shown). Analysis of the middle ear showed that wildtype (n = 2) and Cwe/+ (n = 4) animals had a normal malleus, incus and stapes (Figs. 3A, B). Cwe/Cwe animals (n = 4) had a normal malleus and stapes, but lacked the long process of the incus (Fig. 3C). Analysis of sections through embryos showed that the long process is not present in Cwe/Cwe embryos at E16.5 (data not shown).

Bottom Line: Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion.Lastly we show that Six1 genetically interacts with Jag1.In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

ABSTRACT
Large-scale mouse mutagenesis initiatives have provided new mouse mutants that are useful models of human deafness and vestibular dysfunction. Catweasel is a novel N-ethyl-N-nitrosourea (ENU)-induced mutation. Heterozygous catweasel mutant mice exhibit mild headtossing associated with a posterior crista defect. We mapped the catweasel mutation to a critical region of 13 Mb on chromosome 12 containing the Six1, -4 and -6 genes. We identified a basepair substitution in exon 1 of the Six1 gene that changes a conserved glutamic acid (E) at position 121 to a glycine (G) in the Six1 homeodomain. Cwe/Cwe animals lack Preyer and righting reflexes, display severe headshaking and have severely truncated cochlea and semicircular canals. Cwe/Cwe animals had very few hair cells in the utricle, but their ampullae and cochlea were devoid of any hair cells. Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion. Lastly we show that Six1 genetically interacts with Jag1. We propose that the catweasel phenotype is due to a hypomorphic mutation in Six1 and that catweasel mice are a suitable model for branchio-oto-renal syndrome. In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.

Show MeSH
Related in: MedlinePlus