Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome

Xavier Altafaj, Mara Dierssen, Carmela Baamonde, Eulàlia Martí, Joana Visa, Jordi Guimerà, Marta Oset, Juan Ramón González, Jesús Flórez, Cristina Fillat, Xavier P. Estivill

Research output: Contribution to journalArticle

284 Citations (Scopus)

Abstract

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 craniocaudal 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.

Original languageEnglish
Pages (from-to)1915-1923
Number of pages9
JournalHuman Molecular Genetics
Volume10
Issue number18
Publication statusPublished - 1 Sep 2001
Externally publishedYes

Fingerprint

Down Syndrome
Transgenic Mice
Intellectual Disability
Drosophila
Reversal Learning
Hyperkinesis
Chromosomes, Human, Pair 21
Muscle Hypotonia
Motor Skills
Protein-Serine-Threonine Kinases
Trisomy
Memory Disorders
Brain
Human Chromosomes
Prefrontal Cortex
Short-Term Memory
Diptera
Genes
Complementary DNA
Learning

ASJC Scopus subject areas

  • Genetics

Cite this

Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. / Altafaj, Xavier; Dierssen, Mara; Baamonde, Carmela; Martí, Eulàlia; Visa, Joana; Guimerà, Jordi; Oset, Marta; González, Juan Ramón; Flórez, Jesús; Fillat, Cristina; Estivill, Xavier P.

In: Human Molecular Genetics, Vol. 10, No. 18, 01.09.2001, p. 1915-1923.

Research output: Contribution to journalArticle

Altafaj, X, Dierssen, M, Baamonde, C, Martí, E, Visa, J, Guimerà, J, Oset, M, González, JR, Flórez, J, Fillat, C & Estivill, XP 2001, 'Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome', Human Molecular Genetics, vol. 10, no. 18, pp. 1915-1923.
Altafaj, Xavier ; Dierssen, Mara ; Baamonde, Carmela ; Martí, Eulàlia ; Visa, Joana ; Guimerà, Jordi ; Oset, Marta ; González, Juan Ramón ; Flórez, Jesús ; Fillat, Cristina ; Estivill, Xavier P. / Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 18. pp. 1915-1923.
@article{bb548d602f454fe79d9244e35a38f0b4,
title = "Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome",
abstract = "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 craniocaudal 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.",
author = "Xavier Altafaj and Mara Dierssen and Carmela Baamonde and Eul{\`a}lia Mart{\'i} and Joana Visa and Jordi Guimer{\`a} and Marta Oset and Gonz{\'a}lez, {Juan Ram{\'o}n} and Jes{\'u}s Fl{\'o}rez and Cristina Fillat and Estivill, {Xavier P.}",
year = "2001",
month = "9",
day = "1",
language = "English",
volume = "10",
pages = "1915--1923",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "18",

}

TY - JOUR

T1 - Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome

AU - Altafaj, Xavier

AU - Dierssen, Mara

AU - Baamonde, Carmela

AU - Martí, Eulàlia

AU - Visa, Joana

AU - Guimerà, Jordi

AU - Oset, Marta

AU - González, Juan Ramón

AU - Flórez, Jesús

AU - Fillat, Cristina

AU - Estivill, Xavier P.

PY - 2001/9/1

Y1 - 2001/9/1

N2 - 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 craniocaudal 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.

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 craniocaudal 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.

UR - http://www.scopus.com/inward/record.url?scp=0035445736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035445736&partnerID=8YFLogxK

M3 - Article

C2 - 11555628

AN - SCOPUS:0035445736

VL - 10

SP - 1915

EP - 1923

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

ER -