DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.
The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.
Lepagnol-Bestel
Aude-Marie
AM
INSERM U675, IFR02, Faculté de Médecine Xavier Bichat, Université Paris Diderot-Paris 7, Paris, France.
Zvara
Agnes
A
Maussion
Gilles
G
Quignon
Frédérique
F
Ngimbous
Bedel
B
Ramoz
Nicolas
N
Imbeaud
Sandrine
S
Loe-Mie
Yann
Y
Benihoud
Karim
K
Agier
Nicolas
N
Salin
Paul A
PA
Cardona
Ana
A
Khung-Savatovsky
Suonavy
S
Kallunki
Pekka
P
Delabar
Jean-Maurice
JM
Puskas
Laszlo G
LG
Delacroix
Hervé
H
Aggerbeck
Lawrence
L
Delezoide
Anne-Lise
AL
Delattre
Olivier
O
Gorwood
Philip
P
Moalic
Jean-Marie
JM
Simonneau
Michel
M
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D003712:Dendrites / Q000502:physiology; D004314:Down Syndrome / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor
D002868:Chromosomal Proteins, Non-Histone; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor; C445179:SWI-SNF-B chromatin-remodeling complex