TThese mice carry the spontaneous anx mutation characterized by reduction in body weight, emaciated appearance, and abnormal behavior including head weaving and body tremors, uncoordinated gait, hyperactivity, and poor appetite.Read More +
Compared with their wildtype siblings, anx/anx homozygotes are characterized by a thinning in the neck and tail at 5 days of age, lower body weight detectable by 9 days of age, and death by 22 days of age on the B6C3H-a/a background. Outbreeding to CAST/Ei modifies the phenotype such that homozygotes live to approximately 5 weeks of age. Evaluation of stomach content shows that anx/anx mice ingest less than their siblings. They show headweaving, body tremors, uncoordinated gait, and hyperactivity along with diminished adipose tissue and reduced serum leptin levels. (Maltais et al., 1984; Johansen et al., 2000)
Intraperitoneal injection of 20 day old pups with 5,7-dihydroxytryptamine, a seratonin antagonist, reduces the severity of the neurological phenotypes. Homozygotes have extensive serotonergic hyperinnervation in normal target fields including the hippocampus, frontal cortex, olfactory bulb, and cerebellum, yet they have normal catecholaminergic innervation. This hyperinnervation is thought to reflect increased arborization of axonal fibers since there is no increase in serotonergic cell bodies. In the raphe nuiclues, there are decreased mRNA levels of serotonin transp orter (Slc6a4 previously Htt or 5-Htt) and tryptophan hydroxylase activity is diminished. Similar to food deprived wild type mice, anx/anx mice show decreased mRNA of monoamine oxidase A in the locus ceruleus but not the raphe nuclei. (Maltais et al., 1984; Son et al., 1994; Jahng et al., 1998, Brain Res; Jahng et al., 1998, Dev Brain Res.)
Despite their failure to eat adequately, homozygotes do not show elevated neuropeptide Y mRNA levels in the hypothalamic arcuate nucleus. However, immunohistochemistry revealed increased perikaryal neuropeptide Y staining in the arcuate nucleus and decreased density and neuropeptide Y staining of neuropeptide Y terminals in the paraventricular, arcuate, and other hypothalamic nuclei. Neuropeptide Y staining in the suprachiasmatic and thalamic paraventricular nuclei is normal. There is a similarly altered pattern of expression for agouti gene-related protein with immunoreacitvity increased in the cell body and decreased in the terminals in arcuate neurons despite apparently normal mRNA levels. (Broberger et al., 1997; Jahng et al., 1998, Brain Res; Broberger at el., 1998)
The arcuate nucleus also has a reduction in the number of pro-opiomelanocortin expressing neurons, a reduction in mRNA levels of pro-opiomelanocor tin and neuropeptide Y receptors Y1 and Y5, and a reduction in immunoreactivity of neuropeptide Y receptor Y2, adrenocorticotropic hormone, and alpha melanocyte stimulating hormone. Decreased staining of aspartate, acetylcholinesterase, and somatostatin was also seen in the arcuate nucleus. Decreased staining of cocaine and amphetamine regulated transcript in the arcuate nucleus and other regions of the hyopthalamus has also been reported. This pattern of decreased staining of pro-opiomelanocortin neurons may be due to degeneration of this cell population. No changes in brain cholecystokinin, galanin, or serotonin were detected by immunohistochemistry. (Broberger et al., 1997; Broberger et al., 1999; Johansen et al., 2000.)
The dentate gyrus of anx/anx mice is smaller than normal and has an increase in both the number of proliferating cells and cells undergoing apoptosis according to BrdU and TUNEL assessment. (Kim et al., 2001.)
The spontaneous mutation anorexia was identified in the F2 generation of a cross between DW/J and a wild-derived inbred strain derived from crossing M. m. poschiavinus with an inbred Swiss stock, which contained two Robertsonian translocations Rb(5.15)3Bnr and Rb(16.17)7Bnr. DW/J is homozygous for the agouti (A) allele. After one outcross to C3HeB/FeJ, the anorexia strain was maintained by backcrossing to (C57BL/6J x C3FeLe.B6-a)F1/J, which is homozygous for nonagouti (a). Because anorexia is linked to agouti on Chromosome 2 a carrier breeder could be selected at each generation by simply selecting an agouti mouse. Progeny testing ensured that the mutation was not lost via recombination between anorexia and agouti. Embryos were generated for cryopreservation from heterozygous A anx/a + agouti females bred to heterozygous A anx/a + agouti males. Cryorecovered pups that are black are expected to lack the mutation, while those that are agouti should either be heterozygous carriers suitable for transmitting the mutation or homozygotes that will develop the anorexic phenotype and die before wean age.
|Allele Name||mutation 1|
|Allele Type||Spontaneous (Not Applicable)|
|Gene Symbol and Name||Tyro3, TYRO3 protein tyrosine kinase 3|
|Strain of Origin||various|
|Molecular Note||A single C-to-T transition in the signal sequence causes an arginine to tryptophan substitution at amino acid 13 (p.R13W).|
When using the anorexia mouse strain in a publication, please cite the originating article(s) and include JAX stock #000624 in your Materials and Methods section.
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