Elucidation of the novel functions of EXTL3 involved in the biosynthesis of heparan sulfate in brains and T cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Meijo University
• Principal Investigator: Yamada Shuhei 名城大学, 薬学部, 教授 (70240017)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ヘパラン硫酸 / EXTL3 / ノックアウトマウス / 脳 / T細胞

Outline of Final Research Achievements

The aim of this study is elucidation of the biological roles of EXTL3, a biosynthetic enzyme of heparan sulfate. Brain glutamatergic nerve-specific Extl3-deficient mice were successfully generated and their behavioral as well as physical phenotypes were investigated. So far, typical abnormalities have not been observed. It may be involved in the higher functions in brain. Other enzymes may compensate the enzymatic activity of Extl3. T cell-specific Extl3-deficient mice were also successfully generated. Using the spleenish cells, differentiation of T cells was examined, and it turned out to tend to be immature. Cells of a patient with mutation in EXTL3 were cultured and the amount as well as the disaccharide compositions of glycosaminoglycans from them were examined. Heparan sulfate from the patient was reduced compared with that from a healthy subject.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

ヘパラン硫酸は生体内に普遍的に存在し、細胞の増殖や分化など、非常に基本的な機能に関わっている。ヘパラン硫酸を欠損すると致死となるため、極めて重要な分子である。したがって、ヘパラン硫酸の各臓器における役割の解明は、科学の発展に大いに貢献することができるため、本研究の学術的な意義は極めて大きい。また、EXTL3を欠損した遺伝病の患者の報告例はまだ少ないが、今後さらに見つかってくることが予想される。本研究は、そのような難治性の希少疾患の発症メカニズムの解明や治療法の開発につながる可能性があり、社会的意義は大きい。