DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, we show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Using partially trisomic ES cells, we map this effect to a three-gene segment of HSA21, containing DYRK1A. We independently identify the same locus as the most significant eQTL controlling REST expression in the human genome. We show that specifically silencing the third copy of DYRK1A rescues Rest levels, and we demonstrate altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1A mouse. We reveal that undifferentiated trisomy 21 ES cells show DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest +/-. They produce embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 and a strongly reduced neuroectodermal progenitor compartment. Our results suggest that DYRK1A-mediated deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.
Canzonetta
Claudia
C
Institute of Cell and Molecular Science, Barts & The London, Queen Mary's School of Medicine and Dentistry, University of London, 4 Newark Street, London E1 2AT, UK.
Mulligan
Claire
C
Deutsch
Samuel
S
Ruf
Sandra
S
O'Doherty
Aideen
A
Lyle
Robert
R
Borel
Christelle
C
Lin-Marq
Nathalie
N
Delom
Frederic
F
Groet
Jürgen
J
Schnappauf
Felix
F
De Vita
Serena
S
Averill
Sharon
S
Priestley
John V
JV
Martin
Joanne E
JE
Shipley
Janet
J
Denyer
Gareth
G
Epstein
Charles J
CJ
Fillat
Cristina
C
Estivill
Xavier
X
Tybulewicz
Victor L J
VL
Fisher
Elizabeth M C
EM
Antonarakis
Stylianos E
SE
Nizetic
Dean
D
D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053595:Embryonic Stem Cells / Q000473:pathology* / Q000502:physiology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D039904:Pluripotent Stem Cells / Q000473:pathology / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor
Nat Genet. 1995 Oct;11(2):177-84
7550346
Lancet. 2002 Jan 26;359(9303):310-5
11830198
Science. 1995 Mar 3;267(5202):1360-3
7871435
Nature. 2007 May 31;447(7144):601-5
17468742
Nat Genet. 1997 May;16(1):28-36
9140392
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10458-63
15240883
J Neural Transm Suppl. 2003;(67):139-48
15068246
Cell. 1995 Mar 24;80(6):949-57
7697725
Hum Mol Genet. 2001 Sep 1;10(18):1915-23
11555628
Cell Death Differ. 2007 Mar;14(3):586-96
16858427
Dev Dyn. 2004 Jul;230(3):581-9
15188443
Biochem J. 2003 Apr 1;371(Pt 1):199-204
12534346
Neuroreport. 2007 Mar 26;18(5):441-6
17496800
Cell. 2008 Mar 21;132(6):1049-61
18358816
Nat Rev Genet. 2004 Oct;5(10):725-38
15510164
Nature. 2004 Aug 12;430(7001):743-7
15269782
Nature. 2008 May 8;453(7192):223-7
18362916
Cell. 2005 Sep 23;122(6):947-56
16153702
Nat Neurosci. 2004 Sep;7(9):1003-9
15332090
Hum Mol Genet. 2007 Apr 1;16(7):774-82
17339268
Hum Mol Genet. 2003 Jan 1;12(1):23-32
12490529
Neuropharmacology. 2005 Jul;49(1):122-8
15992587
Stem Cells. 2007 Feb;25(2):354-63
17082226
Nat Genet. 1998 Oct;20(2):136-42
9771705
Hum Mol Genet. 1999 May;8(5):923-33
10196383
Biochem J. 2001 May 1;355(Pt 3):597-607
11311120
Mol Biol Cell. 2005 Dec;16(12):5630-8
16195345
Mol Cell Biol. 2004 Sep;24(18):8018-25
15340064
J Biol Chem. 2000 Jan 28;275(4):2431-8
10644696
Eur J Neurosci. 2008 Mar;27(5):1061-74
18364031
J Neurosci. 2006 Mar 8;26(10):2820-9
16525062
Nature. 2008 Mar 20;452(7185):370-4
18354483
Hum Mol Genet. 2005 Dec 1;14(23):3741-9
16251198
Mol Cell Biol. 2002 Sep;22(18):6636-47
12192061
Neuron. 1995 Feb;14(2):287-301
7857639
Cell. 2005 May 20;121(4):645-657
15907476
Nature. 2003 Jul 10;424(6945):194-7
12853957
Nature. 2006 Jun 1;441(7093):595-600
16554754
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6256-61
9600952
DNA Res. 2005;12(3):203-10
16303751
J Neurosci. 2007 Jun 20;27(25):6729-39
17581960
Genome Res. 2004 Jul;14(7):1268-74
15231743
Am J Hum Genet. 2008 May;82(5):1165-70
18405873
Nat Genet. 2005 Jul;37(7):710-7
15965475
Dev Biol. 2002 Jun 15;246(2):259-73
12051815
Science. 2005 Sep 23;309(5743):2033-7
16179473
Cell. 2004 Mar 19;116(6):779-93
15035981
Biochem Biophys Res Commun. 2001 May 18;283(4):928-32
11350074
BMC Dev Biol. 2007 Nov 29;7:131
18047653
Genome Biol. 2007;8(5):R91
17531092
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5906-11
9159173
Science. 1998 Oct 23;282(5389):744-6
9784132