Targeted disruption of the CCS gene by homologous
recombination. (a) Maps of the wild-type
CCS allele, the targeting vector, and the targeted
CCS locus. Exons 1 to 5 of the CCS gene
are denoted by black boxes. The targeting vector shows the replacement
of exons 1and 2 and flanking genomic sequences including portions of
the promoter by the neomycin gene (neo) and the HSV
thymidine kinase gene (tk). Lines below indicate
expected sizes from a Southern blot for EcoRI-digested
fragments detected with a 5′-probe (black bar) from targeted and
endogenous CCS alleles. B,
BamHI; E, EcoRI; H,
HindIII; S, SalI; X, XhoI.
Arrows denote the sites within the targeted and wild-type
CCS locus from which PCR primers were chosen for
genotyping. (b) Analysis of genomic DNA from ES cells
(lanes 1 and 2) and from progeny of CCS+/−
crosses (lanes 3–5). Genotypes for the CCS targeted
allele and the EcoRI fragments detected for
endogenous (9.5 kb) and targeted (7.2 kb)
CCS alleles with the 5′ probe are indicated.
(c) PCR analysis of DNA extracted from tail clips. By
using primers indicated in a, the 0.4-kb or 0.6-kb
fragment is specific to the endogenous or targeted
CCS allele respectively; wild-type (lane 4),
heterozygous (lanes 1, 2, 3, and 5), and homozygous (lanes 6 and 7)
CCS knockout mice are indicated. (d)
Protein extracts (20 μg) from various tissues of wild-type (lanes 1,
4, 7, 10, and 13), heterozygous (lanes 2, 5, 8, 11, and 14), and
homozygous (lanes 3, 6, 9, 12, and 15) CCS knockout mice
were immunoblotted by using antisera specific for CCS, SOD1, and
α-tubulin. Bound antibodies were detected by using an enhanced
chemiluminescent detection method.