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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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Catweasel mice have posterior crista defects and extra inner hair cells. (A, B) Scanning electron microscopy view of exposed posterior cristae of a wildtype (A) and a Cwe/+ (B) mouse. (C, D) Scanning electron microscopy view of the exposed organ of Corti of a wildtype (C) and Cwe/+ (D) mouse. (E) Quantification of the extra number of inner hair cells observed in wildtype (control) and Cwe/+ (mutant) mice per 100 μm of cochlear duct in the base, middle turn and apex. Standard errors are indicated. Scale bars: A–B = 50 μm; C–D = 25 μm. EC, eminentium cruciatum; IHC, inner hair cell; OHC, outer hair cell.
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fig1: Catweasel mice have posterior crista defects and extra inner hair cells. (A, B) Scanning electron microscopy view of exposed posterior cristae of a wildtype (A) and a Cwe/+ (B) mouse. (C, D) Scanning electron microscopy view of the exposed organ of Corti of a wildtype (C) and Cwe/+ (D) mouse. (E) Quantification of the extra number of inner hair cells observed in wildtype (control) and Cwe/+ (mutant) mice per 100 μm of cochlear duct in the base, middle turn and apex. Standard errors are indicated. Scale bars: A–B = 50 μm; C–D = 25 μm. EC, eminentium cruciatum; IHC, inner hair cell; OHC, outer hair cell.

Mentions: Scanning electron microscopy of the vestibular sensory epithelia showed no obvious abnormalities in the maculae, anterior and lateral cristae of Cwe/+ mice (data not shown). The posterior crista of wildtype mice normally has a non-sensory ridge running in the middle of the sensory patch, called the eminentium cruciatum (Desai et al., 2005; Fig. 1A). In the posterior cristae of Cwe/+ animals this eminentium cruciatum was missing (n = 11; Fig. 1B). There was no obvious difference in the overall size of the sensory region between Cwe/+ animals and controls, but the two ends of the sensory patch were more rounded in shape in Cwe/+ mice than in controls. Three animals scored as Cwe/+ by their headbobbing had an incomplete eminentium cruciatum, indicating that there might be a reduced penetrance for the posterior crista defect in Cwe/+ mice.


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)

Catweasel mice have posterior crista defects and extra inner hair cells. (A, B) Scanning electron microscopy view of exposed posterior cristae of a wildtype (A) and a Cwe/+ (B) mouse. (C, D) Scanning electron microscopy view of the exposed organ of Corti of a wildtype (C) and Cwe/+ (D) mouse. (E) Quantification of the extra number of inner hair cells observed in wildtype (control) and Cwe/+ (mutant) mice per 100 μm of cochlear duct in the base, middle turn and apex. Standard errors are indicated. Scale bars: A–B = 50 μm; C–D = 25 μm. EC, eminentium cruciatum; IHC, inner hair cell; OHC, outer hair cell.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Catweasel mice have posterior crista defects and extra inner hair cells. (A, B) Scanning electron microscopy view of exposed posterior cristae of a wildtype (A) and a Cwe/+ (B) mouse. (C, D) Scanning electron microscopy view of the exposed organ of Corti of a wildtype (C) and Cwe/+ (D) mouse. (E) Quantification of the extra number of inner hair cells observed in wildtype (control) and Cwe/+ (mutant) mice per 100 μm of cochlear duct in the base, middle turn and apex. Standard errors are indicated. Scale bars: A–B = 50 μm; C–D = 25 μm. EC, eminentium cruciatum; IHC, inner hair cell; OHC, outer hair cell.
Mentions: Scanning electron microscopy of the vestibular sensory epithelia showed no obvious abnormalities in the maculae, anterior and lateral cristae of Cwe/+ mice (data not shown). The posterior crista of wildtype mice normally has a non-sensory ridge running in the middle of the sensory patch, called the eminentium cruciatum (Desai et al., 2005; Fig. 1A). In the posterior cristae of Cwe/+ animals this eminentium cruciatum was missing (n = 11; Fig. 1B). There was no obvious difference in the overall size of the sensory region between Cwe/+ animals and controls, but the two ends of the sensory patch were more rounded in shape in Cwe/+ mice than in controls. Three animals scored as Cwe/+ by their headbobbing had an incomplete eminentium cruciatum, indicating that there might be a reduced penetrance for the posterior crista defect in Cwe/+ mice.

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