Generation and characterization of Sca2 (ataxin-2) knockout mice.

Ataxin-2, the gene product of the Spinocerebellar Ataxia Type 2 (SCA2) gene, is a protein of unknown function with abundant expression in embryonic and adult tissues. Its interaction with A2BP1/Fox-1, a protein with an RNA recognition motif, suggests involvement of ataxin-2 in mRNA translation or transport. To study the effects of in vivo ataxin-2 function, we generated an ataxin-2 deficient mouse strain. Ataxin-2 deficient mice were viable. Genotypic analysis of litters from mating of heterozygous mice showed segregation distortion with a significant reduction in the birth of Sca-/- females. Detailed macroscopic and microscopic analysis of surviving nullizygous Sca2 knockout mice showed no major histological abnormalities. On a fat-enriched diet, ataxin-2 deficient animals had increased weight gain. Our results demonstrate that ataxin-2, although widely expressed, is not essential in development or during adult survival in the mouse, but leads to adult-onset obesity.

[1]  H. Zoghbi,et al.  Mice Lacking Ataxin-1 Display Learning Deficits and Decreased Hippocampal Paired-Pulse Facilitation , 1998, The Journal of Neuroscience.

[2]  Pei-shan Wu,et al.  Biochemical and Biophysical Research Communications , 1960, Nature.

[3]  M. LeDoux.  Animal models of movement disorders , 2005 .

[4]  L. Pallanck,et al.  A Drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. , 2002, Genetics.

[5]  Thomas Lengauer,et al.  An integrative approach to gain insights into the cellular function of human ataxin-2. , 2005, Journal of molecular biology.

[6]  S. Pulst,et al.  Identification and expression of a mouse ortholog of A2BP1 , 2001, Mammalian Genome.

[7]  Stefan M Pulst,et al.  Identification and expression of the gene for human ataxin-2-related protein on chromosome 16 , 2003, Experimental Neurology.

[8]  Rudolf Jaenisch,et al.  Chromosomal deletion complexes in mice by radiation of embryonic stem cells , 1997, Nature Genetics.

[9]  J. Priess,et al.  ATX-2, the C. elegans ortholog of ataxin 2, functions in translational regulation in the germline , 2004, Development.

[10]  J. Mulley,et al.  The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene , 2004, Journal of Human Genetics.

[11]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[12]  Thomas Lengauer,et al.  Structural and functional analysis of ataxin-2 and ataxin-3. , 2004, European journal of biochemistry.

[13]  Yves Agid,et al.  Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats , 1996, Nature Genetics.

[14]  S. Tsuji,et al.  Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT , 1996, Nature Genetics.

[15]  S. Pulst,et al.  Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human , 2000, Nature Genetics.

[16]  S. Pulst,et al.  The mouse SCA2 gene: cDNA sequence, alternative splicing and protein expression. , 1998, Human molecular genetics.

[17]  S. Pulst,et al.  A novel protein with RNA-binding motifs interacts with ataxin-2. , 2000, Human molecular genetics.

[18]  D. Hansen,et al.  Caenorhabditis elegans atx-2 Promotes Germline Proliferation and the Oocyte Fate Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession no. AY571963. , 2004, Genetics.

[19]  B. Chait,et al.  Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Luis Velazquez,et al.  Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. , 2005, Brain : a journal of neurology.

[21]  P. Guzmán,et al.  Four distinct classes of proteins as interaction partners of the PABC domain of Arabidopsis thaliana Poly(A)-binding proteins , 2005, Molecular Genetics and Genomics.

[22]  G. Lyons,et al.  Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum? , 2002, Biochemical and biophysical research communications.

[23]  F. Porteu,et al.  Cloning and Characterization of a Family of Proteins Associated with Mpl* , 2002, The Journal of Biological Chemistry.

[24]  Pardis C Sabeti,et al.  Positive Selection of a Pre-Expansion CAG Repeat of the Human SCA2 Gene , 2005, PLoS genetics.

[25]  Stefan M Pulst,et al.  Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death. , 2003, Human molecular genetics.

[26]  F. Westermann,et al.  Ataxin-2 promotes apoptosis of human neuroblastoma cells , 2003, Oncogene.

[27]  C. Stewart,et al.  Simple screening procedure to detect gene targeting events in embryonic stem cells. , 1993, Methods in enzymology.

[28]  G. Kozlov,et al.  Structure and function of the C-terminal PABC domain of human poly(A)-binding protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Pulst,et al.  The ortholog of human ataxin-2 is essential for early embryonic patterning in C. elegans , 2007, Journal of Molecular Neuroscience.

[30]  Georg Auburger,et al.  Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 , 1996, Nature Genetics.

[31]  S. Pulst,et al.  Expression of ataxin‐2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2 , 1999, Annals of neurology.