Our goal is to develop rodent models of human familial motor neuron diseases by expressing the disease genes in transgenic mice. Both dominant and recessive familial motor neuron diseases occur in man. These include familial amyotrophic lateral sclerosis (ALS) which is inherited as an autosomal dominant, and two forms of spinal muscular atrophy (SMA) which show recessive patterns of inheritance. Familial ALS maps to chromosome 21, and the two forms of SMA map to chromosome 5 and to the X-chromosome. The X-linked form of SMA is inherited with an altered androgen receptor which has an unusual CAG repeat. Disease genes with a dominant inheritance pattern are the best candidates for expression of a disease phenotype in mice since they may be active on a wild-type genetic background. Transgenic models of recessively inherited diseases will require that the disease gene be placed on a null mutant background (if a mutation in the mouse gene has already been identified) or that the disease gene is used to replace its mouse counterpart by homologous recombination. Our two objectives in this proposal are 1) to characterize promotors which could be used for targeting expression of dominant disease genes to spinal motor neurons in transgenic mice, and 2) to test if mutant androgen receptors will produce recessive SMA in transgenic mice when bred to the genetic background of testicular feminized (tfm) mice. The glycine receptor is one of very few proteins which are expressed primarily in spinal cord motor neurons. Our initial goal in the project will be to clone upstream flanking sequences of the rat glycine receptor alpha1 subunit (Glyalpha1R) and to evaluate utility for targeting expression of heterologous genes to spinal motor neurons in transgenic mice. Our second goal will be to develop a rodent model of human X- linked SMA.
Our specific aims are:
Specific Aim 1. is to clone the upstream flanking sequences of the rat Glyalpha1R gene.
Specific Aim 2. is to determine if the rat Glyalpha1R promoter contains will target expression of E. coli nlacZ to spinal motor neurons.
Specific Aim 3. is to determine if expression of mutant human androgen receptors with the CAG repeat in transgenic testicular-feminized mice will cause spinal muscular atrophy.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Niemann, S; Landers, J E; Churchill, M J et al. (2008) Motoneuron-specific NR3B gene: no association with ALS and evidence for a common null allele. Neurology 70:666-76
Niemann, Stephan; Kanki, Hiroaki; Fukui, Yasuyuki et al. (2007) Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes. Eur J Neurosci 26:1407-20
Morita, M; Al-Chalabi, A; Andersen, P M et al. (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839-44
Francis, J W; Bastia, E; Matthews, C C et al. (2004) Tetanus toxin fragment C as a vector to enhance delivery of proteins to the CNS. Brain Res 1011:7-13
Francis, Jonathan W; Figueiredo, Dayse; vanderSpek, Johanna C et al. (2004) A survival motor neuron:tetanus toxin fragment C fusion protein for the targeted delivery of SMN protein to neurons. Brain Res 995:84-96
Sapp, Peter C; Hosler, Betsy A; McKenna-Yasek, Diane et al. (2003) Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 73:397-403
Rodriguez, Jorge A; Valentine, Joan S; Eggers, Daryl K et al. (2002) Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. J Biol Chem 277:15932-7
Hayward, Lawrence J; Rodriguez, Jorge A; Kim, Ji W et al. (2002) Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 277:15923-31
Nagai, M; Aoki, M; Miyoshi, I et al. (2001) Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. J Neurosci 21:9246-54
Aoki, M; Liu, J; Richard, I et al. (2001) Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology 57:271-8

Showing the most recent 10 out of 41 publications