These BACHD transgenic mice express a neuropathogenic, full-length human mutant Huntingtin (fl-mhtt) gene modified to harbor a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). These mice may be useful in the testing of candidate therapeutics and in studies examining the contribution of mhtt expression in individual neuronal and non-neuronal cell types in the pathogenesis of Huntington's disease-like phenotypes in vivo.
X. William Yang, University of California Los Angeles
Mice hemizygous for the BACHD transgene are viable and fertile. Under the control of endogenous human htt regulatory machinery, BACHD mice have relatively high expression levels of a neuropathogenic, full-length human mutant Huntingtin (fl-mhtt) modified to harbor a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). Prior to Cre recombinase exposure, BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and selective late-onset neuropathology without somatic polyQ repeat instability in the aged brain. Moreover, BACHD mice reproduce a mhtt aggregation pattern reminiscent of that in adult-onset Huntington's disease (HD). Importantly, a relatively steady-state level of predominantly fl-mhtt and a small amount of mhtt N-terminal fragments present in both the nucleus and cytoplasm, are responsible for the onset and progression of neuropathology. Upon exposure to Cre recombinase, the floxed mhtt-exon1 portion of the transgene is removed and fl-mhtt expression is terminated. These BACHD mice represent a robust in vivo paradigm for studying the HD pathogenesis elicited by fl-mhtt. These mice may be useful in the testing of candidate therapeutics and in studies examining the contribution of mhtt expression in individual neuronal and non-neuronal cell types in the pathogenesis of HD-like phenotypes in vivo.
The 240 kb human bacterial artificial chromosome (BAC) RP11-866L6, containing the entire 170 kb human Huntingtin (htt) genomic locus and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences, was modified by replacing the human htt exon 1 with a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). DNA from a modified BAC clone was used as the source for the BACHD transgene and microinjected into FVB fertilized eggs. Mice from founder line BACHD-I were found to express relatively high levels of full-length human mutant Huntingtin (fl-mhtt) and harbor tandem integrates of approximately 5 copies of the transgene. These BACHD-I transgenic mice were subsequently maintained on the FVB/NJ genetic background for many generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to FVB/NJ inbred mice for at least one generation to establish the colony.
|Expressed Gene||HTT, huntingtin, human|
|Site of Expression|
|Allele Name||transgene insertion I, X William Yang|
|Allele Type||Transgenic (Conditional ready (e.g. floxed), Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||BACHD; BACHD-I|
|Gene Symbol and Name||Tg(HTT*97Q)IXwy, transgene insertion I, X William Yang|
|Promoter||HTT, huntingtin, human|
|Expressed Gene||HTT, huntingtin, human|
|Strain of Origin||FVB|
|Molecular Note||The 240 kb human bacterial artificial chromosome BAC(RP11-866L6), containing the entire 170 kb human Huntingtin (htt) genomic locus and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences, was modified by replacing the human htt exon 1 with a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). DNA from a modified BAC clone was used as the source for the BACHD transgene and microinjected into FVB fertilized eggs. Mice from founder line BACHD-I were found to express relatively high levels of full-length human mutant Huntingtin (fl-mhtt) in the brain by qRT-PCR and the mice harbor tandem integrands of approximately 5 copies of the transgene. Another line, named BACHD-L, was analyzed, showing that the phenotypic aspects of line I were replicated in this strain.|
|Mutations Made By|| |
X. William Yang, University of California Los Angeles
When maintaining a live colony, hemizygous mice may be bred to wildtype siblings or to FVB/NJ inbred mice.
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