These Ugt8a (formerly Cgt) knock-out mice exhibit progressive ataxia, head jerking movements, tremors, and early death.
Brian Popko, University of Chicago
Mice that are homozygous for the targeted mutation have a postnatal lethal phenotype and most do not survive past postnatal day 21 to 28. Surviving homozygotes do not live past 100 days of age. Homozygous female mice are fertile but unable to care for pups. Homozygous male mice are infertile. No gene product (mRNA) is detected by Northern blot analysis of brain tissue from homozygote animals. Mice that are homozygous for the mutation are smaller in size than wildtype and heterozygous littermates. Beginning at 12-14 days of age, homozygotes develop mild ataxia, head jerking movements, and tremors that become more noticeable by 16-20 days of age. The abnormal neurological phenotype is progressive; by 60 days of age many mutants exhibit complete hindlimb paralysis and difficulty breathing. Homozygotes do not synthesize galactolipid galactocerebroside, heterozygotes exhibit reduced levels. Although myelin synthesis and myelin sheath (compact myelin) formation is mostly unaltered in homozygotes, nerve conduction is abnormal in the spinal cord. Electrophysiological analysis of nerve function is consistent with impaired myelin sheath insulative capacity. Histological and electron microscopic analysis reveals vacuolation in the ventral spinal cord and myelin splitting in 24 day old mice. 43 day old mice exhibit more severe myelin splitting, vacuolation of the optic nerve and abnormal node and paranode structure. The electrophysiological and structural abnormalities observed in the CNS are not as severe in the PNS. Levels of peripheral leukocytes and cell numbers in the thymus and spleen are significantly reduced. Spleen, inguinal lymph nodes and Peyer's patches are atrophic. Heterozygotes are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. This mutant mouse strain may be useful in studies of neuroelectrophysiology, nerve myelination and lymphopoiesis in the bone marrow.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 2, which encodes the N-terminal region of the enzyme. The construct was electroporated into 129P2/OlaHsd derived BK4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric male animals were crossed to C57BL/6J mice, and then backcrossed to the same for more than 10 generations.
|Allele Name||targeted mutation 1, Brian Popko|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Cgt-; Cgt0; CGTnull|
|Gene Symbol and Name||Ugt8a, UDP galactosyltransferase 8A|
|Strain of Origin||129P2/OlaHsd|
|Molecular Note||Exon 2 was disrupted by the insertion of a neomycin selection cassette 219 base pairs downstream of the translational start codon. Northern blot analyses showed the exclusive presence of truncated transcript containing the neo transgene in homozgous mutant mice.|
When maintaining a live colony, these mice are bred as heterozygotes due to the homozygous postnatal lethal phenotype. Homozygous female mice are fertile but unable to care for pups. Homozygous male mice are infertile.
When using the Cgt- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004751 in your Materials and Methods section.
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