title: DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model.
abstract: Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS.
authors.affiliation: Molecular Genetics Research Laboratory, Graduate School of Science The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kurabayashi
authors.affiliation: Departments of Clinical Neurosciences, Cell Biology & Anatomy, Biochemistry & Molecular Biology, Calgary, Hotchkiss Brain Institute University of Calgary, Alberta, Canada.
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.affiliation: Molecular Genetics Research Laboratory, Graduate School of Science The University of Tokyo, Bunkyo-ku, Tokyo, Japan kamon_sanada@gen.s.u-tokyo.ac.jp.
authors.forename: Kamon
authors.initials: K
authors.lastname: Sanada
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000502:physiology; D002454:Cell Differentiation; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D019579:Neocortex / Q000473:pathology / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D050791:STAT Transcription Factors; D000097603:Dyrk Kinases
keywords: DYRK1A; Down syndrome; STAT; astrogliogenesis; neocortical progenitor