2022 Fiscal Year Final Research Report
Inka2 regulates actin dynamics in neuronal development
| Project/Area Number |
19K06931
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 46020:Anatomy and histopathology of nervous system-related
|
|---|
| Research Institution | Waseda University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2023-03-31
|
| Keywords | ニューロン / アクチン骨格 / 樹状突起スパイン / Pakファミリー / Inka2 |
|---|
| Outline of Final Research Achievements |
Inka2 gene is a novel mammalian protein exhibiting sequence similarity to Inka1, which serves as a possible inhibitor for Pak4. We found that Inka2-iBox directly binds to Pak4 catalytic domain to suppress actin polymerization. Inka2 promoted actin depolymerization and inhibited the formation of cellular protrusion caused by Pak4 activation. We further generated the conditional knockout mice of the Inka2 gene. The beta-galactosidase reporter indicated the preferential Inka2 expression in the dorsal forebrain neurons. Cortical pyramidal neurons of Inka2-/- mice exhibited decreased density and aberrant morphology of dendritic spines with marked activation/phosphorylation of downstream molecules of Pak4 signal cascade, including LIMK and Cofilin. These results uncovered the unexpected function of endogenous Pak4 inhibitor in neurons. Unlike Inka1, Inka2 is a critical mediator for actin reorganization required for dendritic spine development.
|
| Free Research Field |
神経科学
|
| Academic Significance and Societal Importance of the Research Achievements |
神経細胞の樹状突起スパインの適切な個数や形態は、Pakファミリーシグナルを介するアクチン細胞骨格のダイナミックな重合・脱重合制御により厳しく管理されている。この制御機構の破綻は、統合失調症や自閉スペクトラム症、アルツハイマー病などの種々の精神疾患や発達障害などの機序に深く関係する。しかしその制御機構には未解明な点が多い。本研究によりInka2が、脳内におけるPak4阻害因子であることが明らかとなった。今後Inka2が関与する疾患発症の原因解明やInka2によるPak４阻害をターゲットとする創薬開発へつながることが期待される。
|
