STOCK a Tyrp1^b Pmel^si/J

Stock number: 000064
Product name: silver brown and silver grey

Research areas: Cancer Research, Cell Biology Research, Dermatology Research, Mouse/Human Gene Homologs

Description

This strain is currently unavailable due to replenishing of cryopreserved stocks. Interested customers who register interest will be contacted when the strain is again available.

 

“Silver brown” (a/a b/b si/si) and "silver grey" (a/a B/b si/si) mice exhibit a lightened brown or black silvered coat color due to defects in melanin production. Animals homozygous for Pmel^si are severely depleted of PMEL (premelanosome protein) and are of potential use in studies of the development of non-pathogenic amyloid protein and melanoma cancers.

Detailed description

Premelanosome protein (PMEL; also called Si, Pmel17, GP87 (mouse), and GP100 (human), among many other names) is crucial to the normal production of melanin pigment in melanocytes. The protein forms an internal fiber matrix that, though it shares features of amyloids associated with neurodegenerative diseases, is itself a non-pathogenic amyloid (Fowler, 2006; Watt, 2013). The protein is formed in endosomal-derived melanosome compartments of melanocytes where the fibers organize into parallel sheets that serve as a scaffold for melanin synthesis, sequestering and condensing melanin pigment (Bissig, 2016). Mice lacking PMEL or expressing a mutant form of the protein show varying degrees of hypopigmentation and their pigment cells exhibit reduced viability in the hair bulb follicle (Watt, 2013).

The si (silver) mutation of the mouse Pmel gene incorporates a G to A nucleotide substitution (GenBank AF119092), creating a premature stop codon in the cytoplasmic tail region and truncating the protein (Martínez-Esparza, 1999). The mutation blocks internalization of the protein from the plasma membrane and inhibits the formation of PMEL fibrils. Melanosomes in the melanocytes of homozygous Pmel^si mice are severely depleted of PMEL (Theos, 2006; Watt, 2013).

Hairs from “silver brown” (a/a b/b si/si) mice that are homozygous for the nonagouti (a), brown (Tyrp1^b), and silver (Pmel^si) alleles display an overall lightened brown coat color with white-tipped hairs (some hairs may be all-white). In black/"silver grey" mice heterozygous for brown (B/b), the effect of si is greatly intensified; a/a B/b si/si animals are reported to be lighter than either B/B (non-brown) or b/b (brown) silver mice (Dunn and Thigpen, 1930). Some young mice may have a dark first pelage, but all are said to become progressively lighter (more silvered) with age, the males showing more silvering than females (Silvers, 1979).

High levels of PMEL expression are associated with poor survival outcomes in human skin cutaneous melanoma (SKCM) (Zhang, 2021). A secreted form of the PMEL protein has been used as a specific serum marker. Early studies demonstrated that follicular melanocytes of silver mice are more susceptible to damage resulting from X-irradiation (Chase, 1950).

Development

A "silver grey" stock was acquired by Dunn and Thigpen (Dunn and Thigpen, 1930; Silvers, 1979) in 1927 from a single pair of mice from the house mouse colony, where the mutation arose, maintained by English fancier William Turton. Silver (Dunn-MacDowell-Gowen) was subsequently maintained in LGW inbred mice at Iowa State University and was bred into the linkage stock carrying Pcdh15^av/Pcdh15^av, Si^si/Si^si, Tyrp1^b/+, a^e/a^e (RH Schaible, 1957). Pcdh15^av is a mutation that arose on the K strain in 1955 and linkage with the silver locus was demonstrated (Schaible, 1961); extreme non-agouti, a^e, appeared in mice descending from x-ray mutagenized male breeders of the S strain (Hollander and Gowen, 1956).

In 1963, this "av" linkage stock was imported from RH Schaible to the Jackson Laboratory where mice were sibling mated for 14 generations. A single outcross to C57BL/10Gn occurred in 1968 and mice were sibling mating thereafter; Pcdh15^av has not been detected in this stock since the outcross. In 1979 at about F50, "silver brown" males (a/a, Tyrp1^b/Tyrp1^b, Si^si/Si^si) were outcrossed to female B6C3Fe-a/a F1 mice for frozen embryo storage. In 1987, B6C3Fe-a/a X STOCK a Tyrp1^b Si^si embryos were thawed and a live stock reconstituted. These mice were sibling mated [F1p] F3 through F5 to generate additional embryo stocks in 1988.

Allele

Symbol: Pmel^si
Name: silver
MGI accession ID: MGI:1857040
Generation method: Spontaneous
Marker symbol: Pmel
Marker name: premelanosome protein
Chromosome: 10
Strain of origin: Not Specified
Molecular note: Sequencing of partial gp87 cDNA from homozygous mutant melanocytes showed this mutation comprises a G to A substitution at base 1808, resulting in a premature stop codon and truncation of the protein in the C-terminal cystolic domain.
General note: This mutation arose in an unspecified English fancy stock.

Allele

Symbol: Tyrp1^b
Name: brown
MGI accession ID: MGI:1855960
Generation method: Spontaneous
Marker symbol: Tyrp1
Marker name: tyrosinase-related protein 1
Chromosome: 4
Strain of origin: old mutant of the mouse fancy
Molecular note: A G-to-A transition point mutation at position 329 was shown by revertant analysis to be responsible for the mutant phenotype seen in the brown mutant. This mutation changes cysteine to tyrosine at position 110 (p.C110Y) in the encoded protein. Three other point mutations in the brown sequence were identified, but do not contribute to the mutant phenotype.

Allele

Symbol: a
Name: nonagouti
MGI accession ID: MGI:1855937
Generation method: Spontaneous
Marker symbol: a
Marker name: nonagouti
Chromosome: 2
Strain of origin: old mutant of the mouse fancy
Molecular note: Characterization of this allele shows an insertion of DNA comprised of a 5.5kb virus-like element, VL30, into the first intron of the agouti gene. The VL30 element itself contains an additional 5.5 kb sequence, flanked by 526 bp of direct repeats (beta4 retroviral sequence). The host integration site is the same as for a^t-2Gso and A^w-38J and includes a duplication of four nucleotides of host DNA and a deletion of 2 bp from the end of each repeat. Northern analysis of mRNA from skin of homozygotes shows a smaller agouti message and levels 8 fold lower than found in wild-type.
General note: Insertion of the LV30 retrotransposon without the beta4 retrovirus sequence does not cause the nonagouti phenotype. J:278039