2022 Fiscal Year Final Research Report
Elucidating novel molecular mechanisms of neuromuscular disorders due to impaired ribosomal rRNA processing
| Project/Area Number |
21K20745
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0802:Biomedical structure and function and related fields
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| Research Institution | Juntendo University |
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Principal Investigator |
Ichino Noriko 順天堂大学, 大学院医学研究科, 特任研究員 (40649365)
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| Project Period (FY) |
2021-08-30 – 2023-03-31
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| Keywords | ribosome / H/ACA ribonucleoprotein / gar1 / skeletal muscle / developmental biology / zebrafish |
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| Outline of Final Research Achievements |
gar1 is a gene involved in the function of ribosomes, but the pathogenic mechanism caused by its deficiency is unknown. In this study, we analyzed the mechanism of cell death induction in gar1 mutant showing developmental abnormalities in skeletal muscle and eyes. When translation of p53 protein was suppressed by microinjection of morpholino antisense oligonucleotide, microphthalmia tended to improve, but skeletal muscle impairment did not improve. This suggests that p53-independent cell death is induced skeletal muscle and both p53-dependent and p53-independent mechanisms of cell death are induced in the eyes. In addition, the expression level of p53 isoform Δ113p53 was increased in gar1 mutant, but it also had no effect on inhibition of cell death by p53. In conclusion, there is a tissue specificity in the mechanism of developmental abnormalities in skeletal muscle and eyes caused by gar1 deficiency, which may be related to the characteristic phenotype of ribosomal disease.
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| Free Research Field |
発生生物学
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| Academic Significance and Societal Importance of the Research Achievements |
ゼブラフィッシュgar1変異体には、他のリボソーム病のゼブラフィッシュ病態モデルと共通する発生異常だけでなく、著名な骨格筋発生異常が新たに見出されたが、その病態メカニズムは不明であった。本研究では、分子生物学的な手法を用いて、gar1変異体に特徴的な骨格筋病態がp53非依存的細胞死であることを示し、この骨格筋細胞死メカニズムの組織特異性を初めて明らかにした。リボソームは全ての細胞に重要なオルガネラであるが、リボソーム病には組織特異性があることから、本研究で見出された知見は、リボソーム病の病態メカニズムにおける組織特異性を解き明かすための重要なマイルストーンであると考えている。
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