RRC ID |
64542
|
著者 |
Fujitani M, Zhang S, Fujiki R, Fujihara Y, Yamashita T.
|
タイトル |
A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484/protocadherin-19 signaling.
|
ジャーナル |
Mol Psychiatry
|
Abstract |
Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder. The underlying molecular mechanism of this genetic variation remained unknown, but its core genetic locus-conserved across mice and humans-contains seven genes. Here, we generated bacterial artificial chromosome-transgenic mice carrying a human 16p13.11 locus, and these mice showed the behavioral hyperactivity phenotype. We identified miR-484 as the responsible gene using a combination of expression and functional analyses. Mature miR-484 was expressed during active cortical neurogenesis, and overexpression of miR-484 decreased proliferation and increased neural progenitor differentiation in vivo. Luciferase screening identified the 3'-untranslated region of protocadherin-19 (Pcdh19) as a target of miR-484. The effect of miR-484 on neurogenesis was rescued by ectopic PCDH19 expression. These results demonstrate that miR-484 promotes neurogenesis by inhibiting PCDH19. Dysregulation of neurogenesis by imbalanced miR-484/PCDH19 expression contributes to the pathogenesis of 16p13.11 microduplication syndrome.
|
巻・号 |
22(3)
|
ページ |
364-374
|
公開日 |
2017-3-1
|
DOI |
10.1038/mp.2016.106
|
PII |
mp2016106
|
PMID |
27378146
|
PMC |
PMC5322274
|
MeSH |
Animals
Attention Deficit Disorder with Hyperactivity / genetics*
Cadherins / genetics
Cadherins / metabolism
Cell Differentiation
Chromosomes, Human, Pair 16 / genetics
Developmental Disabilities / genetics
Gene Duplication / genetics
Genetic Predisposition to Disease / genetics
Humans
Hyperkinesis
Mice
Mice, Transgenic
MicroRNAs / genetics*
MicroRNAs / metabolism*
Neurogenesis / genetics
Protocadherins
Risk Factors
Signal Transduction / genetics
|
IF |
12.384
|
リソース情報 |
ヒト・動物細胞 |
293T(RCB2202) |