title: Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice.
abstract: Overexpression of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A), encoded by a gene located in the Down syndrome (DS) critical region, is considered a major contributor to developmental abnormalities in DS. DYRK1A regulates numerous genes involved in neuronal commitment, differentiation, maturation, and apoptosis. Because alterations of neurogenesis could lead to impaired brain development and mental retardation in individuals with DS, pharmacological normalization of DYRK1A activity has been postulated as DS therapy. We tested the effect of harmine, a specific DYRK1A inhibitor, on the development of neuronal progenitor cells (NPCs) isolated from the periventricular zone of newborn mice with segmental trisomy 16 (Ts65Dn mice), a mouse model for DS that overexpresses Dyrk1A by 1.5-fold. Trisomy did not affect the ability of NPCs to expand in culture. Twenty-four hours after stimulation of migration and neuronal differentiation, NPCs showed increased expression of Dyrk1A, particularly in the trisomic cultures. After 7 days, NPCs developed into a heterogeneous population of differentiating neurons and astrocytes that expressed Dyrk1A in the nuclei. In comparison with disomic cells, NPCs with trisomy showed premature neuronal differentiation and enhanced γ-aminobutyric acid (GABA)-ergic differentiation, but astrocyte development was unchanged. Harmine prevented premature neuronal maturation of trisomic NPCs but not acceleration of GABA-ergic development. In control NPCs, harmine treatment caused altered neuronal development of NPCs, similar to that in trisomic NPCs with Dyrk1A overexpression. This study suggests that pharmacological normalization of DYRK1A activity may have a potential role in DS therapy.
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA. bozena.mazur-kolecka@opwdd.ny.gov
authors.forename: Bozena
authors.initials: B
authors.lastname: Mazur-Kolecka
authors.forename: Adam
authors.initials: A
authors.lastname: Golabek
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kida
authors.forename: Ausma
authors.initials: A
authors.lastname: Rabe
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Hwang
authors.forename: Tatyana
authors.initials: T
authors.lastname: Adayev
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.forename: Michael
authors.initials: M
authors.lastname: Flory
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kaczmarski
authors.forename: Elaine
authors.initials: E
authors.lastname: Marchi
authors.forename: Janusz
authors.initials: J
authors.lastname: Frackowiak
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006247:Harmine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009030:Mosaicism; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014314:Trisomy / Q000235:genetics; D000097603:Dyrk Kinases
chemical_list: D001973:Bromodeoxyuridine; D005904:Glial Fibrillary Acidic Protein; D005968:Glutamate Decarboxylase; D006247:Harmine; D008996:Monoamine Oxidase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C401141:glutamate decarboxylase 2