Hemizygous male and homozygous female Harlequin mice are nearly bald with eventual, noticeable ataxia. These mice are characterized by delayed cerebellar cortical atrophy with an apoptotic loss of granule cells, a necrotic loss of Purkinje cells, and retinal degeneration. These mice may be useful in studies of neurodegenerative degeneration including Alzheimer's disease.Read More +
Harlequin mice exhibit paucity of fur resulting in near baldness in hemizygous males and homozygous females. Heterozygous females have a patchy absence of hair that is not always obvious, since the degree of hair loss is notably less than 50%. Homozygotes and hemizygous males weigh less than heterozygous or wild type controls. Ataxia is noticeable by 5 months and progresses as the mice age. Initially the ataxia manifests itself as a side-to-side, unsteady gait with a lateral tremor visible at rest. A delayed cerebellar cortical atrophy has been characterized in these mutants, with an apoptotic loss of granule cells beginning at 4 months of age and a necrotic loss of Purkinje cells occurring subsequently. The granule cells re-enter the cell cycle, but the Purkinje cells do not, supporting the postulate that inappropriate cell cycle re-entry of terminally differentiated neurons can induce apoptosis. Cell loss is greater in the caudal lobules of the cerebellum and is extensive by 9 to 11 months of age. Retinal degeneration is found beginning with ganglion and amacrine cell loss in the ganglion cell layer at 3 months of age, and progresses with cell loss in the inner and outer nuclear layers and reduction of rod and cone ERG responses at 4 months of age. By 10 months, the rod and cone ERG responses are gone, and at 11 months of age there isapparent cell loss in all layers of the retina. No cerebellar or retinal abnormalities were found in heterozygous females. Catalase activity and expression and total glutathione levels are increased in the cerebella of mutant mice, but not in other brain regions, and lipid hydroperoxidases are increased in brain and heart tissue. Primary granule cell cultures, but not cortical cultures, from harlequin mice show increased sensitivity to peroxide. Hemizygous males, homozygous females and hemizygous females are all viable and fertile. (Barber 1971; Falconer and Isaacson 1972; Bronson et al., 1990; Klein et al., 2002.)
The harlequin mutation, Aifm1Hq, arose spontaneously in the non-inbred stock CF-1 in the laboratory of Dr. B. R. Barber, Milano, Italy, who first reported in 1971. It was imported into The Jackson Laboratory before February, 1978 and was maintained for years by crossing a female (C57BL/6J-Aw-J x CBA/CaGnLe)F1 to an Aifm1Hq/Y male then intercrossing a heterozygous female with a wildtype male. In 1983 embryos were generated for cryopreservation by crossing hemizygous (Aifm1Hq/Y) males with C57BL/6J females. Thus, cryo-recoverd mice will have a greater percentage of C57BL/6J-derived alleles than CBA/CaGnLe-derived alleles and all males will be wildtype and all of the females will be heterozygous.
|Allele Synonym(s)||Hq; Pcdc8hq|
|Gene Symbol and Name||Aifm1, apoptosis-inducing factor, mitochondrion-associated 1|
|Strain of Origin||CF-1|
|General Note||Although initial reports indicated that ataxia was more severe in males than females, later unpublished reports indicate that there is no significant difference in severity of the ataxia phenotype between hemizygous males and homozygous females (S. Ackerman, personal communication)|
|Molecular Note||The harlequin mutation is an ecotropic proviral insertion at the Pdcd8 gene. This insertion leads to an 80% decrease in transcipt and protein levels, relative to wild-type controls.|
Comments: Hq/Y males need to stay with their mothers an extra week or more because they are too small to wean at 3 weeks.
When using the harlequin mouse strain in a publication, please cite the originating article(s) and include JAX stock #000501 in your Materials and Methods section.