論文 - 詳細
| RRC ID | 31354 |
|---|---|
| 著者 | Kurabayashi N, Sanada K. |
| タイトル | Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells. |
| ジャーナル | Genes Dev |
| Abstract |
Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS. |
| 巻・号 | 27(24) |
| ページ | 2708-21 |
| 公開日 | 2013-12-15 |
| DOI | 10.1101/gad.226381.113 |
| PII | 27/24/2708 |
| PMID | 24352425 |
| PMC | PMC3877759 |
| MeSH | Animals Calcium-Binding Proteins Cell Differentiation / genetics* Disease Models, Animal Down Syndrome / genetics Down Syndrome / pathology Gene Dosage / genetics* Gene Expression Intracellular Signaling Peptides and Proteins* / genetics Intracellular Signaling Peptides and Proteins* / metabolism Mice Muscle Proteins* / genetics Muscle Proteins* / metabolism NFATC Transcription Factors / metabolism Neocortex / cytology* Neocortex / embryology Neurogenesis / genetics* Plasmids / genetics Protein Serine-Threonine Kinases* / genetics Protein Serine-Threonine Kinases* / metabolism Protein-Tyrosine Kinases* / genetics Protein-Tyrosine Kinases* / metabolism Stem Cells / cytology* |
| IF | 9.527 |
| 引用数 | 29 |
| WOS 分野 | DEVELOPMENTAL BIOLOGY GENETICS & HEREDITY CELL BIOLOGY |
| リソース情報 | |
| 遺伝子材料 | Dyrk1a/pCAGEN (RDB12851) Dscr1-pCAGEN(Dscr1.1L/pCAGEN) (RDB12852) Dyrk1a sh#1/psilencer3.1-puro (RDB12853) Dyrk1a sh#2/psilencer3.1-puro (RDB12854) Dscr1 sh#1/pBS-U6 (RDB12855) Dscr1 sh#2/pBS-U6 (RDB12856) NFATc4(FL)/pCAGEN (RDB12857) NFATc4(CA)/pCAGEN (RDB12858) NFATc4(DN)/pCAGEN (RDB12859) GFP-NFATc4(FL)/pCAGEN (RDB12860) |