PMID- 11555628
DA - 20010913
DCOM- 20011204
IS - 0964-6906
VI - 10
IP - 18
DP - 2001 Sep 1
TI - Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.
PG - 1915-23 AB - Down's syndrome (DS) is a major cause of mental retardation, hypotonia and delayed development. Murine models of DS carrying large murine or human genomic fragments show motor alterations and memory deficits. The specific genes responsible for these phenotypic alterations have not yet been defined. DYRK1A, the human homolog of the Drosophila minibrain gene, maps to the DS critical region of human chromosome 21 and is overexpressed in DS fetal brain. DYRK1A encodes a serine-threonine kinase, probably involved in neuroblast proliferation. Mutant Drosophila minibrain flies have a reduction in both optic lobes and central brain, showing learning deficits and hypoactivity. We have generated transgenic mice (TgDyrk1A) overexpressing the full-length cDNA of Dyrk1A. TgDyrk1A mice exhibit delayed cranio-caudal maturation with functional consequences in neuromotor development. TgDyrk1A mice also show altered motor skill acquisition and hyperactivity, which is maintained to adulthood. In the Morris water maze, TgDyrk1A mice show a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect turned out to be specifically related to reference memory, whereas working memory was almost unimpaired. These alterations are comparable with those found in the partial trisomy chromosome 16 murine models of DS and suggest a causative role of DYRK1A in mental retardation and in motor anomalies of DS.
AD - Down Syndrome Research Group, Medical and Molecular Genetics Center, IRO,
Hospital Duran i Reynals, Gran Via s/n, Km 2.7, 08907-L'Hospitalet de
Llobregat, Barcelona, Catalonia, Spain.
FAU - Altafaj, X
AU - Altafaj X
FAU - Dierssen, M
AU - Dierssen M
FAU - Baamonde, C
AU - Baamonde C
FAU - Marti, E
AU - Marti E
FAU - Visa, J
AU - Visa J
FAU - Guimera, J
AU - Guimera J
FAU - Oset, M
AU - Oset M
FAU - Gonzalez, J R
AU - Gonzalez JR
FAU - Florez, J
AU - Florez J
FAU - Fillat, C
AU - Fillat C
FAU - Estivill, X
AU - Estivill X
LA - eng
PT - Journal Article
CY - England
TA - Hum Mol Genet
JID - 9208958
RN - EC 2.7.1.- (Dyrk kinase)
RN - EC 2.7.1.- (Protein-Serine-Threonine Kinases)
RN - EC 2.7.1.112 (Protein-Tyrosine Kinase)
SB - IM
MH - Animal
MH - Animals, Newborn
MH - Behavior, Animal/physiology
MH - Brain/metabolism/pathology
MH - Cognition Disorders/*genetics
MH - Disease Models, Animal
MH - Down Syndrome/*genetics/pathology/physiopathology
MH - Female
MH - Gene Expression Regulation
MH - Genotype
MH - Human
MH - Male
MH - Maze Learning/physiology
MH - Memory/physiology
MH - Mental Retardation/*genetics
MH - Mice
MH - Mice, Inbred C57BL
MH - Mice, Transgenic
MH - Motor Activity/physiology
MH - Protein-Serine-Threonine Kinases/*genetics
MH - Protein-Tyrosine Kinase/*genetics
MH - Psychomotor Disorders/*genetics
MH - Support, Non-U.S. Gov't
EDAT- 2001/09/14 10:00
MHDA- 2002/01/05 10:01
URLF- http://hmg.oupjournals.org/cgi/content/full/10/18/1915
URLS- http://hmg.oupjournals.org/cgi/content/abstract/10/18/1915
PST - ppublish
SO - Hum Mol Genet 2001 Sep 1;10(18):1915-23.