High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.
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.
Institute for Systems Biology, Seattle, WA, USA.|Institute for Genome Sciences and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Seth A
SA
Ament
Institute for Systems Biology, Seattle, WA, USA.|Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.
Jocelynn R
JR
Pearl
McLaughlin Research Institute, Great Falls, MT, USA.
Andrea
A
Grindeland
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Jason
J
St Claire
Institute for Systems Biology, Seattle, WA, USA.|Department of Computer Science, University of Washington, Seattle, WA, USA.
John C
JC
Earls
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Marina
M
Kovalenko
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Tammy
T
Gillis
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Jayalakshmi
J
Mysore
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
James F
JF
Gusella
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Jong-Min
JM
Lee
CHDI Management/CHDI Foundation, Princeton, NJ, USA.
Seung
S
Kwak
CHDI Management/CHDI Foundation, Princeton, NJ, USA.
David
D
Howland
Institute for Systems Biology, Seattle, WA, USA.
Min Young
MY
Lee
Institute for Systems Biology, Seattle, WA, USA.
David
D
Baxter
Institute for Systems Biology, Seattle, WA, USA.
Kelsey
K
Scherler
Institute for Systems Biology, Seattle, WA, USA.
Kai
K
Wang
Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA.
Donald
D
Geman
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Jeffrey B
JB
Carroll
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Marcy E
ME
MacDonald
McLaughlin Research Institute, Great Falls, MT, USA.
George
G
Carlson
Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Vanessa C
VC
Wheeler
Institute for Systems Biology, Seattle, WA, USA.
Nathan D
ND
Price
Institute for Systems Biology, Seattle, WA, USA.
Leroy E
LE
Hood
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D000068617:Genetic Background; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein / Q000096:biosynthesis / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D059467:Transcriptome / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C506812:Htt protein, mouse; D000071058:Huntingtin Protein