Htt Conditional Knockout mouse models

Huntington disease work centers on Htt, the mouse ortholog of human HTT, encoding huntingtin, a 350 kDa HEAT-repeat scaffold that organizes vesicular and axonal transport along microtubules through HAP1 and the dynein/dynactin machinery, sustains BDNF transcription by sequestering REST in the cytoplasm, and supports selective autophagy cargo recognition and ciliogenesis. Pathology follows CAG repeat expansion in exon 1 beyond roughly 36 units, generating an elongated polyglutamine tract that drives aggregation, aberrant exon 1 splicing into a highly toxic fragment, and somatic repeat instability in striatal medium spiny neurons through MSH3 and mismatch repair activity. Because complete Htt loss is embryonic lethal near gastrulation, conditional floxed alleles are mandatory for adult loss-of-function and lowering-safety studies, whereas full-length or humanized exon 1 CAG knockins preserve endogenous regulation for instability and biomarker endpoints far better than randomly integrated transgenes. Align allele class with endpoint, pairing neuron-restricted or striatum-restricted Cre drivers with region-specific silencing questions.

Htt conditional knockout mice carry a floxed allele so you delete function only where Cre is active. The germline allele stays intact until you cross to a tissue specific Cre. Labs reach for this design when a global knockout is lethal, when they need adult onset loss, or when regional redundancy hides a whole body phenotype.