Mutations at the Kit locus affect various aspects of hematopoiesis, the proliferation and migration of primordial germ cells and melanoblasts during development. This double mutant strain carries flexed tail along with the original KitW mutation, which is characterized by lethality in most homozygotes with severe macrocytic anemia and a phenotype referred to as 'black-eyed-white' in surviving homozygotes. Heterozygotes have near normal blood parameters with a white belly spot.Read More +
This strain is homozygous for f.
Flexed tail homozygotes can be identified hematologically as earlyas embryonic day 13 and are detectably paler than normal by embryonic day 16, with most paler than normal by embryonic day 15. Homozygotes are small at birth and have a transitory siderocytic hypochromic anemia due to defective heme synthesis in fetal but not adult reticulocytes. Fetal erythrocytes have more alpha hemoglobin synthesis than beta hemoglobin synthesis. Very high numbers of siderocytes are found at birth and this decreases during the first few weeks of life and stabilizes at approximately 3 weeks of age with 3% siderocytes, significantly higher than in wildtype adults. Most homozygotes have a belly spot and 1 to 5 flexures in the tail due to vertebral fusions. Vertebral fusions are also found elsewhere in the vertebral column. Fewer than expected homozygotes are generated indicating prenatal death and the postnatal death rate is approximately 4 times normal. A small minority of homozygotes have been found to have embryonic neural tube defects or a dorsal enlargement of the head.
The FL/1Re inbred strain, homozygous for f and wildtype for Kit, was made from a female WB/Re heterozygous for KitW bred to a male heterozygous for f from a partially inbred stock derived from crosses between C3H/J and Snell?s WA linkage-testing stock. The integrated FL/1Re congenic strain, segregating for both KitW and f, was derived by repeated backcross-intercross to the developing FL/Re inbred. To generate this FL/1Re segregating congenic a female from the F1 generation of FL/Re heterozygous for KitW and homozygous for f was backcrossed to a WC/Re inbred wildtype for both Kit and f and a Kit wildtype f heterozygous offspring was bred to the F2 generation of the incipient FL/1Re inbred (Russell and McFarland, 1966). This strategy of maintenance, backcrossing KitW carriers to f/f of the FL/1Re homozygous inbred, was maintained for several decades, with this strain reaching generation N58 in 1974, and in 1980 embryos were generated for cryopreservation from +/+ f/f FL/1Re inbred females at generation F79 and KitW/+ f/+ and KitW/+ +/+ congenic males at generation N81.
|Allele Name||dominant spotting|
|Gene Symbol and Name||Kit, KIT proto-oncogene receptor tyrosine kinase|
|Strain of Origin||old mutant of the mouse fancy|
|General Note||This is an old mutant of the mouse fancy. KitW mutants are a potential model for human inherited pure red cell anemia, called Diamond-Blackfan anemia (OMIM 205900), but mouse mutants do not respond to corticosteroid treatment as do human patients. Thus, the mechanism of anemia causation in the two conditions must be different (J:14286).|
|Molecular Note||A G-to-A substitution at the first nucleotide at the 5' boundary of intron 10 following the transmembrane exon 10 results in two different aberrantly spliced transcripts putatively expressed in a tissue specific manner. A deletion of 107 bp was found in transcripts from mast cells of mutant mice. A deletion of 234 bp was found in transcripts from brain or bone marrow cells. The mutation disrupts splice donotr site G-GT by changing it to G-AT point, thereby causing exon skipping. The 107 bp deletion could have resulted from skipping of a transmembrane region exon and the 234 bp deletion from skipping 3 exons. The 107 bp deletion would create a frame shift with a stop codon 12 bp downstream, whereas the larger deletion would still be in frame. Northern blot analysis indicated that mast cells from mutants have only 31-37% of the transcripts as mast cells derived from normal bone marrow, suggesting that the mutation may reduce efficiency and authenticity of transcription and splicing.|
|Allele Name||flexed tail|
|Gene Symbol and Name||f, flexed-tail|
|Strain of Origin||Not Specified|
|General Note|| |
The flexed-tail mutation appeared in a stock maintained by Dr. H.R. Hunt at Michigan State College (J:12951). Homozygotes are small at birth and have a transitory hypochromic, microcytic anemia characterized by a large number of siderocytes containing non-heme iron granules. Most homozygotes also have flexed tail and a belly spot, but these are not constant manifestations of the mutant. Because of the anemia there is probably greater postnatal mortality among f/f than among normal mice (J:14979).
The anemia begins on the 12th day of embryonic life when the liver first starts to produce blood cells (J:14979). It is most intense at 15 days of gestation and still severe at birth, but by 2 weeks of age has disappeared. Although adults have normal blood values, their response to hemopoietic stress is defective (J:5439, J:27511).
The results of numerous studies have led to the conclusion that the prenatal deficiency in number of erythrocytes and the defective response of adult erythropoietic cells are due to a delay in maturation of already committed erythroid stem cells, and that earlier uncommitted precursors are unaffected by f (J:5439, J:5654, J:5582).
An additional effect of f in homozygotes is defective heme synthesis, which occurs in fetal reticulocytes but not in adult reticulocytes nor in erythroblasts at earlier stages of maturation. In fetal reticulocytes there is normal uptake of iron but poor incorporation into hemoglobin (J:5439), probably as a result of reduced activity of delta-aminolevulinate synthetase and dehydratase (J:5591).
Fetal erythrocytes of f/f mice have more alpha than beta globin chains. In both f/f and wild-type fetal erythrocytes there is more alpha- than beta-chain mRNA; probably some regulatory mechanism bringing about equal alpha- and beta-chain synthesis exists in wild-type mice but is defective in f/f (J:5827, J:30711).
The tail abnormalities are first noticeable on the 14th day of gestation as abnormal differentiation of the intervertebral discs (J:13090). The possibility that abnormal heme synthesis could cause the tail and pigment defects in f/f mice has been discussed (J:5591).
It was suggested that flexed-tail might be a mutation in the mouse homolog Fancc of the gene defective in human Fanconi anemia, complementation group C, but no mutation in the Fancc gene or abnormalities in Fancc mRNA have been detected in f/f mutants (J:13598). Also, flexed-tail mice are not susceptible to increases in chromosomal aberrations induced by mitomycin C, a characteristic of Fancc mutant mice (J:35839).
This allele arose on a genetically undefined stock in 1927 and was subsequently transferred onto several genetic backgrounds to create the congenic and recombinant inbred lines Je/Le-f/f, FL1/ReJ, WB/ReJ-f/f and C57BL/6J-f/f. The phenotypes listed above might be associated with any of these strains; in most cases it was not specified.
|Molecular Note||Note that two conflicting reports (J:68377 and J:98445/J:128616) state that the underlying genetic defect in the flexed tail mouse is either in the Sfxn1 or the Smad5 gene.|
|Mutations Made By|| |
Mark Fleming, Children's Hospital Boston