Dosage of the Abcg1-U2af1 region modifies locomotor and cognitive deficits observed in the Tc1 mouse model of Down syndrome

PLoS One. 2015 Feb 23;10(2):e0115302. doi: 10.1371/journal.pone.0115302. eCollection 2015.

Abstract

Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / genetics*
  • Animals
  • Chromosomes, Mammalian
  • Cognition / physiology
  • Cognition Disorders / genetics*
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • Gait Disorders, Neurologic / genetics*
  • Gene Dosage
  • Genotype
  • Lipoproteins / genetics*
  • Maze Learning / physiology
  • Mice
  • Motor Activity / genetics*
  • Nuclear Proteins / genetics*
  • Phenotype
  • Reversal Learning / physiology
  • Ribonucleoproteins / genetics*
  • Rotarod Performance Test
  • Splicing Factor U2AF
  • Telomere

Substances

  • ABCG1 protein, mouse
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Lipoproteins
  • Nuclear Proteins
  • Ribonucleoproteins
  • Splicing Factor U2AF
  • U2AF2 protein, human
  • Zrsr1 protein, mouse

Grants and funding

The National Centre for Scientific Research is a public research agency in France, The European commission funded the AnEUploidy project (LSHG-CT-2006-037627) and the Foundation Jerome Lejeune granted the authors some funding. Nevertheless the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.