The CrTflox (Slc6a8fl) conditional allele has loxP sites flanking the regions encoding the 2nd-4th transmembrane domain of the creatine transporter gene on the X chromosome. These CrTflox mice are a Cre-lox tool for generating tissue-specific CrT deletions, and may be useful for studying creatine transport and human X-linked creatine deficiency syndrome, mental retardation, autism, and speech, language, cognitive, and memory disorders.
Joseph F Clark, University of Cincinnati
|Allele Type||Gene Symbol||Gene Name|
|Targeted||Slc6a8||solute carrier family 6 (neurotransmitter transporter, creatine), member 8|
The CrTflox (also called Slc6a8fl) conditional allele has loxP sites flanking exons 2-4 of the creatine transporter gene on the X chromosome. When bred to mice that express Cre recombinase, the resulting offspring will have deletion of the floxed sequences (encoding the 2nd-4th transmembrane domain of CrT) deleted in the cre-expressing tissues. Homozygous females (CrTflox/flox) and hemizygous males (CrTflox/Y) are viable and fertile with no observed abnormalities.
These CrTflox mice are a Cre-lox tool for generating tissue-specific CrT deletions, and may be useful for studying creatine transport and human X-linked creatine deficiency syndrome, mental retardation, autism, and speech, language, cognitive, and memory disorders.
For example, breeding CrTflox mice to a strain expressing Cre recombinase in embryonic tissues results in offspring with the ubiquitous CrT knockout allele (CrT-). Pan deletion males (CrT-/Y) lack creatine in the brain and muscle, have significant creatine reductions in other tissues, and exhibit learning and memory deficits resembling human CrT deficiency. Pan deletion mice are available at The Jackson Laboratory Repository as Stock No. 021072.
Similarly, breeding CrTflox mice to animals expressing Cre recombinase in cortex and hippocampus (such as Camk2a-Cre; Stock No. 005359 for example) results in mice with CrT function inactivated in the predominant brain areas of cognition and memory. The resulting males exhibit impaired cognitive function, but normal balance and musculoskeletal control systems (similar to human patients). Treatment with the creatine analog cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) results in rescued cyclocreatine and cyclocreatine phosphate expression in the brain and profound improvement in cognitive abilities (novel object recognition, spatial learning and memory tests).
A targeting vector was designed by Dr. Joseph F. Clark (University of Cincinnati) to insert a loxP site upstream of exon 2, and an frt-flanked neo cassette and second loxP site downstream of exon 4 of the creatine transporter gene (CrT; Slc6a8) on the X chromosome. The construct was electroporated into C57BL/6-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient MF-1 blastocysts. Chimeric males were bred with C57BL/6J females to generate the conditional founder mice. To remove the frt-flanked neo cassette, mice were bred with the germline FLP deleter strain (B6;SJL-Tg(ACTFLPe)9205Dym/J; Stock No. 003800). The resulting mice with the CrTflox allele (also called Slc6a8fl) have a loxP site upstream of exon 1, and a single frt site and second loxP site downstream of exon 4. The CrTflox mice were bred to C57BL/6J wildtype mice for several generations (and the FLP transgene was removed) prior to sending to The Jackson Laboratory Repository in 2013. Upon arrival, sperm was cryopreserved. To generate the living CrTflox colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J female mice (Stock No. 000664). The CrTflox colony was then maintained by breeding homozygous females with hemizygous males.
|Allele Name||targeted mutation 1.1, Joseph Clark|
|Allele Type||Targeted (Conditional ready (e.g. floxed), No functional change)|
|Gene Symbol and Name||Slc6a8, solute carrier family 6 (neurotransmitter transporter, creatine), member 8|
|Gene Synonym(s)||AA589632; CCDS1; CHOT1; CHT1; CRT; CRTR; CT1; CTR5; Creat; Creat; creatine transporter; expressed sequence AA589632|
|Strain of Origin||C57BL/6|
|Molecular Note||A loxP site was inserted upstream of exon 2. An FRT-flanked neo cassette with a 3' loxP site was inserted downstream of exon 4. Flp-mediated recombination removed the neo cassette, leaving exons 2, 3, and 4 floxed.|
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