Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice
| Autor: | Yu-Wen Hwang, Elizabeth Kida, Ausma Rabe, Adam A. Golabek, Tatyana Adayev, Janusz Frackowiak, Michael Flory, Wojciech Kaczmarski, Bozena Mazur-Kolecka, Elaine Marchi, Jerzy Wegiel |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Monoamine Oxidase Inhibitors
Time Factors DYRK1A Cellular differentiation Mice Transgenic Trisomy Protein Serine-Threonine Kinases Biology Mice Cellular and Molecular Neuroscience Neural Stem Cells Cell Movement Glial Fibrillary Acidic Protein otorhinolaryngologic diseases medicine Animals Progenitor cell Cells Cultured Glial fibrillary acidic protein Glutamate Decarboxylase Mosaicism Neurogenesis Gene Expression Regulation Developmental Trisomy 16 Cell Differentiation Protein-Tyrosine Kinases medicine.disease Neural stem cell Cell biology Disease Models Animal Harmine stomatognathic diseases medicine.anatomical_structure Animals Newborn Bromodeoxyuridine nervous system biology.protein Down Syndrome Neuroscience Chromosomes Human Pair 16 Astrocyte |
| Zdroj: | Journal of Neuroscience Research. 90:999-1010 |
| ISSN: | 0360-4012 |
| DOI: | 10.1002/jnr.23007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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