Ashen mice have a lightened coat color that is gray on a non-agouti background similar to that of dilute (Myo5ad) or leaden (ln) mutants. Lane and Womack reported that on an agouti background the yellow pigment is more dilute in ashen mice resulting in a grayer agouti than that found in dilute or leaden mice, but Wu et al. subsequently reported that dilute and ashen mice have identical degrees of coat color dilution. This pigment dilution results from defective trafficking of melanosomes that are normally found throughout the dendrites of melanocytes. Similar to that seen in leaden mutants, ashen melanosomes are clumped around the nucleus and sparse in the dendrites where normally they are released. Melanosome trafficking from the melanocyte cell body to the ends of the dendrites results from a microtubule-based bidirectional transport. MYO5A is essential for retaining the melanosomes in the ends of the dendrites and preventing their retrograde transport ba...
Read More +Genetic Background | Generation |
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Allele Type | Gene Symbol | Gene Name |
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Spontaneous | Rab27a | RAB27A, member RAS oncogene family |
Allele Type | Gene Symbol | Gene Name |
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Spontaneous | Clcc1 | chloride channel CLIC-like 1 |
Ashen mice have a lightened coat color that is gray on a non-agouti background similar to that of dilute (Myo5ad) or leaden (ln) mutants. Lane and Womack reported that on an agouti background the yellow pigment is more dilute in ashen mice resulting in a grayer agouti than that found in dilute or leaden mice, but Wu et al. subsequently reported that dilute and ashen mice have identical degrees of coat color dilution. This pigment dilution results from defective trafficking of melanosomes that are normally found throughout the dendrites of melanocytes. Similar to that seen in leaden mutants, ashen melanosomes are clumped around the nucleus and sparse in the dendrites where normally they are released. Melanosome trafficking from the melanocyte cell body to the ends of the dendrites results from a microtubule-based bidirectional transport. MYO5A is essential for retaining the melanosomes in the ends of the dendrites and preventing their retrograde transport back toward the cell body. In ashen mice MYO5A fails to colocalize with melanosomes indicating that RAB27A is required in some way to facilitate this association. (Lane and Womack, 1979; Wu et al., 1998 and 2001.)
Ashen mice have increased bleeding times and their platelets have fewer platelet dense granules and less serotonin than normal. This has not been reported for leaden or dilute mice. Diminished target cell lysis is found using ashen CTLs and NK cells. This is due to diminished granule exocytosis although Fas-Fas ligand mediated CTL cytotoxicity appears to be normal. Polarization of these ashen lytic granules is normal, but they fail to dock at the target membrane. Mice with the dilute mutation have normal CTL activity. (Wilson et al., 2001; Haddad et al., 2001; Stinchcombe et al., 2001.)
Griscelli syndrome in humans is characterized by pigmentary dilution of the skin and hair due to defective melanosome release from melanocytes. This syndrome has been associated with mutations in either RAB27A or MYO5A. In cases with mutations in RAB27A the disease does not have a neurological component, but does include haemophagocytic syndrome, a severe activation of T cells and macrophages. In cases with mutations in MYO5A the disease includes severe neurological impairment but no immunological defects. This variation in disease phenotype is paralleled in mice with mutations in these genes. Thus, certain mutations in Myo5a are models for Griscelli syndrome with neurologic impairment and the ashen mutation (Rab27aash) is a model for Griscelli syndrome with hemophagocytic syndrome. (Manasche et al., 2000; Pastural et al., 2000.)
The Clcc1m1J spontaneous mutation, which causes increased sensitivity to endoplasmic reticulum stress in the cerebellum, was identified in C3H/HeSnJ (Jia et al., 2015) and has been found homozygous in all C3H/HeSn strains assessed at The Jackson Laboratory, including this ashen mutant subline that separated from the parental inbred in 1975.
The ashen (Rab27aash) mutation arose spontaneously in strain C3H/HeSn at F85 in 1975 at the Jackson Laboratory. The mutation was maintained on the C3H/HeSn background by forced heterozygosis (mating a heterozygote x a homozygote). It was cryopreserved in 1980 by mating heterozygous females with homozygous males to generate embryos. It was removed from the shelf in 1995.
Allele Name | ashen |
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Allele Type | Spontaneous |
Allele Synonym(s) | ash |
Gene Symbol and Name | Rab27a, RAB27A, member RAS oncogene family |
Gene Synonym(s) | |
Strain of Origin | C3H/HeSn |
Chromosome | 9 |
Molecular Note | Sequence analysis of the coding region revealed an A-to-T transversion in the third base pair of the splice donor site downstream of exon 4. This results in activation of two cryptic downstream splice donor sites and the addition of intronic sequence into mis-spliced Rab27a mRNA. |
Allele Name | mutation 1, Jackson |
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Allele Type | Spontaneous |
Allele Synonym(s) | nm2453; sprawler |
Gene Symbol and Name | Clcc1, chloride channel CLIC-like 1 |
Gene Synonym(s) | |
Strain of Origin | C3H/HeSnJ |
Chromosome | 3 |
Molecular Note | The mutation is an intracisternal A-particle (IAP) retrotransposon insertion into a C3H/HeSnJ genomic region. The IAP is inserted into intron 2 of the gene and disrupts the normal splicing of the mRNA transcribed from this gene. Resulting in-frame stop codons from the insertion of IAP sequences resulted in severely reduced protein levels in mutant tissues. The retrotransposition of this IAP is a recent event occurring during, or after, the establishment of the C3H/HeSn substrain. |
When using the ashen mouse strain in a publication, please cite the originating article(s) and include JAX stock #000120 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous or Homozygous for Rab27a<ash>, 1 pair minimum |
Frozen Mouse Embryo | C3H/HeSn-Rab27a<ash>/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | C3H/HeSn-Rab27a<ash>/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | C3H/HeSn-Rab27a<ash>/J Frozen Embryos | $3373.50 |
Frozen Mouse Embryo | C3H/HeSn-Rab27a<ash>/J Frozen Embryos | $3373.50 |
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