title: DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
abstract: 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.
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Canzonetta
authors.forename: Claire
authors.initials: C
authors.lastname: Mulligan
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruf
authors.forename: Aideen
authors.initials: A
authors.lastname: O'Doherty
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lin-Marq
authors.forename: Frederic
authors.initials: F
authors.lastname: Delom
authors.forename: Jürgen
authors.initials: J
authors.lastname: Groet
authors.forename: Felix
authors.initials: F
authors.lastname: Schnappauf
authors.forename: Serena
authors.initials: S
authors.lastname: De Vita
authors.forename: Sharon
authors.initials: S
authors.lastname: Averill
authors.forename: John V
authors.initials: JV
authors.lastname: Priestley
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Martin
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.forename: Gareth
authors.initials: G
authors.lastname: Denyer
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Dean
authors.initials: D
authors.lastname: Nizetic
mesh_terms: 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
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor
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