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DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2008 Sep; Vol. 83 (3), pp. 388-400. Date of Electronic Publication: 2008 Sep 04. - Publication Year :
- 2008
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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.
- Subjects :
- Animals
Cell Differentiation
Disease Models, Animal
Down Syndrome genetics
Down Syndrome pathology
Embryonic Stem Cells physiology
Gene Expression Regulation, Developmental
Humans
Mice
Mice, Transgenic
Pluripotent Stem Cells pathology
Pluripotent Stem Cells physiology
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases genetics
Quantitative Trait Loci
Repressor Proteins genetics
Dyrk Kinases
Down Syndrome metabolism
Embryonic Stem Cells pathology
Gene Dosage
Protein Serine-Threonine Kinases physiology
Protein-Tyrosine Kinases physiology
Repressor Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 83
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 18771760
- Full Text :
- https://doi.org/10.1016/j.ajhg.2008.08.012