Dense time series gene expression data from striatum of Huntington’s disease CAG knock-in mice across multiple genetic backgrounds. Mus musculus

Huntington’s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+ mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis. Overall design: Huntington's disease mouse model with CAG expansion in Htt compared to wildtype littermate controls; mouse striatum sampled weekly (n=1-5 per week depending on group) from 4 weeks of age to 20 weeks of age. C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds. Included Htt.Q111/+ and WT in each strain and additional shorter CAG lengths Htt.Q92/+ and Htt.Q50/+ in the C57BL/6J background. Total n =791 mice.