Homozygous mice die several hours after birth, exhibiting truncated forelimbs, absent hindlimbs, and transparent skin with a complete lack of hair follicles. Newborn heterozygotes have 50% decreased oral epithelial thickness, mildly thinner epidermis, and do not express keratin-6. Heterozygous mice show accelerated aging and decreased life span with severe skin lesions.
IMR Colony, The Jackson Laboratory
Mills 1999 Nature 398:708 describes the homozygous phenotype on a mixed B6-Tyrc-Brd;129S7(129S5) background. Further, they do not distinguish between the two targeted alleles (pTV6H(90)-generated p63Brdm1 [Trp63tm1Brd] or pTV12E(60)-generated p63Brdm2 [Trp63tm2Brd]) as both "produced an identical phenotype." Homozygous mice are born alive, but die several hours after birth. No transcripts have been detected in homozygotes. They have striking developmental defects, exhibiting truncated forelimbs, absent hindlimbs, and transparent skin with a complete lack of hair follicles. Both the gross and histological appearance of internal organs is normal. Functional permeability of the skin is dramatically increased; homozygous mice lose thirty times more water than normal littermates. It is presumed that death occurs from dehydration. Heterozygous mice are viable, fertile, and do not exhibit any overt developmental defects. Newborn heterozygotes have 50% decreased oral epithelial thickness, mildly thinner epidermis, and do not express keratin-6.
Keyes et al 2005 Genes Dev 19:1986 describes the phenotype of heterozygous mice used in aging studies. They exclusively used p63Brdm2 (Trp63tm2Brd) mice on a mixed B6-Tyrc-Brd;129S7(129S5) background. Heterozygous mice show accelerated aging and decreased life span with severe lesions of the skin, tongue, rectum, cervix and cornea. Infection of the skin, subcutaneous tissues, oropharynx, and genitourinary tract are also significant. Older mice can also develop chronic nephritis which closely resembles age-related human kidney disease.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
The pTV12E(60) targeting vector, containing a keratin 14 promoter-driven Agouti minigene, a non-functional 3' portion of an hprt cassette, a single loxP site, a puromycin resistance gene, and a 129S5-derived DNA fragment containing Trp63 exons 5, 6 and 10, was used for gap repair gene targeting of the endogenous gene. This construct was inserted into the exon 10 region by electroporation into 129S7/SvEvBrd-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J-Tyrc-Brd blastocysts. The resulting chimeric males were bred to C57BL/6J-Tyrc-Brd females. Mutant mice were on a mixed B6;129 genetic background were sent to The Jackson Laboratory. Upon arrival, mutant mice were bred to C57BL/6J for more than 10 generations to generate this congenic strain.
|Allele Name||targeted mutation 2, Allan Bradley|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||p63Brdm2; p63KO|
|Gene Symbol and Name||Trp63, transformation related protein 63|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||An integration vector disrupts the reading frame within exon 10. Northern blot analysis on homozygous mutant animals indicates that an mRNA transcript is not produced from this allele.|
|Mutations Made By|| |
Dr. Alea Mills, Cold Spring Harbor Laboratory