Abstract
BackgroundPathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored.Methodology/Principal FindingsWe used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals.Conclusions/SignificanceThe present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21.
Highlights
Aneuploidies are associated with several human diseases that affect specific brain areas, leading to mild or severe mental retardation
Our experiments indicate that haploinsufficiency of Dual Specificity Tyrosine-Regulated Kinase-1A (Dyrk1A) might contribute to the impairment of cognitive functions and adaptative behavior of human monosomy 21
Morris Water Maze In the Morris water maze (MWM), both Dyrk1A+/2 and wild type mice showed a significant reduction of the escape latency along the four sessions of the acquisition phase (MANOVA, ‘‘session’’: F(3–32) = 24.2, P,0.0001)
Summary
Aneuploidies are associated with several human diseases that affect specific brain areas, leading to mild or severe mental retardation. Most of the detected cases of monosomy 21 correspond to partial monosomies, suggesting that critical chromosomal regions or haploinsufficient genes may be responsible for the observed phenotypes. A more detailed study of unrelated individuals with overlapping partial deletions of chromosome 21 [4,8] has indicated an 8.4-Mb region in chromosome band 21q22.2–22.3 (KCNJ6-COL6A2) as responsible for cortical dysplasia and mental retardation leading to the proposal that one or more dosage-sensitive genes in this region contribute to cortical development and cognition. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored
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