2022 Fiscal Year Final Research Report
Physiological functions and pathogenic mechanisms of Rac3, an intellectual disability-associated G protein, in cerebral development
| Project/Area Number |
21K15895
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Nagoya University (2022)
Institute for Developmental Research Aichi Developmental Disability Center (2021) |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Keywords | 知的障害 / 神経発達 / 子宮内胎児脳電気穿孔法 / Gタンパク質 / Rhoファミリー / Rac3 / PAK1 / アクチン細胞骨格 |
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| Outline of Final Research Achievements |
RAC3 variants are associated with neurodevelopmental disorders (NDD) and brain anomalies. To elucidate the pathophysiological mechanisms of RAC3-related NDD, we examined the effects of pathogenic variants on the development of mouse cerebral cortex. In vitro analysis revealed that all tested RAC3 variants were active, with varying affinities for downstream effectors. We then focused on the 4 variants affecting the Switch II region, common to other Rho family GTPases. Each RAC3 variant expressed using in utero electroporation caused defects in cortical neuron morphology and migration. Dominant negative PAK1 rescued the defects, suggesting that impaired RAC3→PAK1 signaling is a pathophysiological mechanism underlying RAC3-related NDD. Our results indicate that the RAC3 variants result in morphological and functional defects in cortical neurons during brain development, eventually leading to the clinical features of the NDD.
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| Free Research Field |
神経化学、小児神経
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| Academic Significance and Societal Importance of the Research Achievements |
1)RAC3異常症が、大脳皮質形成時の神経細胞移動障害を背景とする病態であること、2)病因シグナルの一つとしてRAC3→PAK1を特定したこと、3)PAK1抑制は、RAC3変異体による異常表現型を回復できる可能性を示したこと、が本研究の成果である。すなわちRAC3関連神経疾患において、PAK1は創薬ターゲットであり、PAK1阻害剤は創薬シーズになる可能性を示すことができた。本研究成果はRAC3異常による知的障害発症機序を正確に理解する上で重要な知見であると共に、創薬シーズを発見できたことは大きな臨床的意義がある。
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