This inbred mutant strain carries mahogany (Atrnmg) and limb deformity (Fmnld-J) in repulsion. Limb deformity is characterized by single long bones replacing the tibia and fibula, and the ulna and radius. Mahogany is characterized by darkened pigmentation, increased locomotor activity, decreased body weight, and vacuolization and myelination defects in the central nervous system.Read More +
This strain is segregating for Grem1ld-J and Atrnmg, which are maintained in repulsion.
Attractin (ATRN) deficiencies cause darkened pigmentation, increased locomotor activity, decreased body weight, and vacuolization and myelination defects in the central nervous system.
Agouti protein competes with alpha-melanocyte stimulating hormone (a-MSH) for binding of melanocortin 1 receptor (MC1R), and this in turn signals pigment type switching from eumelanin production to pheomelanin production. ATRN interacts with agouti possibly to facilitate the interaction with MC1R. In mice, ATRN deficiencies result in decreased pheomelanin production causing darkened ears, tail, feet, and coat color which becomes dark reddish brown as these mice age. Thus, the initial Atrn mutation reported by Lane and Green was called mahogany (Atrnmg). ATRN deficiencies darken the coloring caused by nonagouti such that these mice are coal black with no white hairs behind the ears or around the perineum and have blacker ears, tail, and feet. ATRN deficiency can suppress the impact on coat color of the Ay allele but not the Mc1re allele. The Atrnmg allele is hypomorphic while the Atrnmg-3J allele results from a deletion that is thought to yield a null mutation. While both alleles cause darkened coat color due to decreased pheomelanin production, the increased severity of the Atrnmg-3J allele is evident in the coat color of mahogany mice carrying the yellow allele of agouti: Ay Atrnmg/A Atrnmg mice are dark brown on the back but yellow on the belly while Ay Atrnmg-3J/A Atrnmg-3J mice are entirely black with dark ears and tail. (He et al., 2001.)
In the central nervous system, alpha melanocortin hormone (a-MSH) interacts with MC4R, and agouti related protein competes with a-MSH for binding to MC4R. These interactions are important for the regulation of body weight. Agouti protein, which is normally expressed only in the skin, can compete with a-MSH for binding to MC4R. Thus, mice carrying the Ay allele which causes systemic expression of Agouti protein are hyperphagic and develop hyperinsulinemia, hyperleptinemia, hyperglycemia, increased linear growth, and obesity. Atrnmg and Atrnmg-3J have each been shown to suppress some or all of these Ay induced characteristics. While the mahogany mutations are generally characterized as recessive, Miller et al. reported that Atrnmg can suppress in a semidominant manner both the coat color and obesity induced by Ay. Dinulescu et al. reported that mice homozygous for Atrnmg on a C57BL/6J congenic background have increased nighttime locomotor activity, a 0.5 degree increase in body temperature, and increased basal metabolic rate, and are hyperphagic. Gunn et al. reported that mice homozygous for Atrnmg-3J on the C3H/HeJ background and mice homozygous for Atrnmg on a C3H/HeJ congenic background also have increased nighttime locomotor activity but that they have normal food intake and decreased body weight associated with decreased adiposity. Mice homozygous for Atrnmg-3J have decreased fat storage and are resistant to weight gain when fed a high fat diet. Atrn mutations do not alter the obesity caused by a null mutation of Mcr4 or transgenic expression of Agouti related protein, nor do they inhibit obesity caused by the tub, Cpefat, Leprob or Leprdb alleles. (Nagle et al., 1999; He et al., 2001; Dinulescu et al., 1998.)
In addition to their coat color changes and metabolic changes, Atrn deficient mice also have been found to have vacuolization in brain tissue. He et al. reported finding 5-40uM vacuoles in both the gray and white matter of mice homozygous for the Atrnmg-3J allele on a segregating background of C3H/HeJ and C57BL/6J. These were found in the brainstem, cerebellar medulla, granular layer of the cerebellum, pons, thalamus, hippocampus, caudate and putamen, somatosensory cortex and spinal cord gray matter, and fewer were found in the primary motor cortex, visual cortex, and white matter tracts of the spinal cord. Transgenic expression of attractin driven by the Beta-actin promoter prevented this phenotype in mice homozygous for Atrnmg-3J but did not cause any additional obvious phenotype. Kuramoto et al. found vacuoles up to 10-20uM in diameter widely distributed in the brainstem, cerebral cortex, cerebellum, and spinal cord of 40 day old mice homozygous for the Atrnmg-3J allele on the C3H/HeJ background. They also described aberrant myelination and a mild tremor (17 Hz) in the adults. Bronson et al. found vacuoles in brain samples of mice homozygous for the Atrnmg, Atrnmg-3J, and Atrn6J alleles as well as Atrnmg/Atrnmg-6J and Atrnmg-3J/Atrnmg-6J heterozygotes. The severity of this phenotype increased with age and varied between strains. By two months of age, vacuoles were found in the granule layer of the cerebellar cortex, deeper layers of the cerebral cortex, and various nuclei of the medulla, midbrain, and thalamus, and by nine months of age vacuoles were found throughout the brain. These vacuoles were generally not found in white matter tracts. Electron microscopy showed vacuoles in the axons, dendrites, and neuronal soma. Myelination defects specific to the central nervous system were found in mice homozygous for the mg-6J allele of Atrn but not other mutant alleles of Atrn. Bronson et al. also described severe tremors and a sprawling gait in Atrnmg-6J/Atrnmg-6J mice on the CAST/Ei background and decreased severity after backcrossing to C3H/SnJ. They also found that Atrnmg-3J/Atrnmg-3J mice are prone to "seizures that begin with a sudden freezing of motion and progress to tonic-clonic movements". They did not find seizures in Atrnmg/Atrnmgmice. In the rat, the zitter allele of attractin has been found to cause hypomyelination and vacuolization in the central nervous system resulting in early-onset tremor. (Kuramoto et al., 2001.)
|Allele Name||limb deformity Jackson|
|Allele Synonym(s)||Fmnld-J; footless; ldJ|
|Gene Symbol and Name||Grem1, gremlin 1, DAN family BMP antagonist|
|Strain of Origin||CBA/Ca-Bmp5se|
|Molecular Note||A G-to-A transition mutation at the boundary between intron 1 and exon 2 disrupts pre-mRNA splicing by eliminating the AG motif at the 3' splice acceptor site. The aberrant transcript expressed by this allele has a 65 base deletion of the 5' part of exon 2 and is missing the translational start codon.|
|Gene Symbol and Name||Atrn, attractin|
|Strain of Origin||C3H x Swiss stock|
|Molecular Note||This allele comprises a 5 kb insertion in a 3' to 5'orientation in intron 26, downstream of the exons encoding the transmembrane domain. The insertion was identified as an intracisternal A particle (IAP) transposon. Northern hybridization results predict that the insertion affects normal splicing. Western analysis of whole brain extracts from homozygous mice show an Atrn protein that migrates slightly faster than normal Atrn.|
Atrn and Fmn are linked on chromosome 2. This strain is homozygous for the non-agouti (a) allele and is maintained with mahogany (Atrnmg) and limb deformity (Fmnld-J) in repulsion. During the progeny test, pregnant females must be checked daily for Fmnld-J/Fmnld-J pups in order to be certain they carry the Fmnld-J allele.
When using the LDJ/LeJ mouse strain in a publication, please include JAX stock #000289 in your Materials and Methods section.
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