ENU mutagenesis screen to establish motor phenotypes in wild-type mice and modifiers of a pre-existing motor phenotype in tau mutant mice.
Modifier screening is a powerful genetic tool. While not widely used in the vertebrate system, we applied these tools to transgenic mouse strains that recapitulate key aspects of Alzheimer's disease (AD), such as tau-expressing mice. These are characterized by a robust pathology including both motor and memory impairment. The phenotype can be modulated by ENU mutagenesis, which results in novel mutant mouse strains and allows identifying the underlying gene/mutation. Here we discuss this strategy in detail. We firstly obtained pedigrees that modify the tau-related motor phenotype, with mapping ongoing. We further obtained transgene-independent motor pedigrees: (i) hyperactive, circling ENU 37 mice with a causal mutation in the Tbx1 gene-the complete knock-out of Tbx1 models DiGeorge Syndrome; (ii) ENU12/301 mice that show sudden jerky movements and tremor constantly; they have a causal mutation in the Kcnq1 gene, modelling aspects of the Romano-Ward and Jervell and Lange-Nielsen syndromes; and (iii) ENU16/069 mice with tremor and hypermetric gait that have a causal mutation in the Mpz (Myelin Protein Zero) gene, modelling Charcot-Marie-Tooth disease type 1 (CMT1B). Together, we provide evidence for a real potential of an ENU mutagenesis to dissect motor functions in wild-type and tau mutant mice.
Alzheimer's and Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia.
Xin
X
Liu
Michael
M
Dobbie
Rob
R
Tunningley
Belinda
B
Whittle
Yafei
Y
Zhang
Lars M
LM
Ittner
Jürgen
J
Götz
D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D005684:Gait / Q000235:genetics; D060045:Genes, Modifier / Q000235:genetics*; D006948:Hyperkinesis / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics* / Q000378:metabolism; D009069:Movement Disorders / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D018993:Myelin P0 Protein / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D014202:Tremor / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D018993:Myelin P0 Protein; D016875:tau Proteins