Elucidation of the molecular mechanism of maxillofacial hypoplasia caused by FAT1 gene mutation

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19629
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: The University of Tokushima
• Principal Investigator: KUDO Yasusei 徳島大学, 大学院医歯薬学研究部(歯学域), 教授 (50314753)
• Co-Investigator(Kenkyū-buntansha): 毛利 安宏 徳島大学, 大学院医歯薬学研究部(歯学域), 講師 (80464353) ; 北島 正二朗 慶應義塾大学, 政策・メディア研究科(藤沢), 特任講師 (00452590)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: FAT1 / 顎顔面形成 / ソニックヘッジホッグ

Outline of Final Research Achievements

We generated Fat1 KI mice mimicking gene mutations frequently observed in oral cancer patients and found that they exhibit severe mandibular and tongue formation defects. Since the mandible and tongue develop from the first pharyngeal arch, we conducted morphological and transcriptome analyses. Between embryonic days 9.5 and 10.5, we observed the disappearance of the midline structure in the central region of the first pharyngeal arch and abnormal gene expression patterns in this region. Furthermore, we clarified that abnormalities in the Hedgehog signaling pathway, mediated by YAP/TAZ activation downstream of Fat1, are involved in the mandibular and tongue formation defects.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

Fat1 KIマウスにおける顎顔面形成異常に、Fat1シグナル下流のTEADによる遺伝子発現抑制がShh遺伝子発現を低下させ、第1咽頭弓の形成不全を引き起こすことを明らかにした。ヒトFAT1の遺伝子変異は、頭頸部扁平上皮癌のみならず、顔面の形態異常、目および手足の指に形態異常を示すことが知られている。 本研究成果は、頭頸部扁平上皮癌の診断・治療への応用や遺伝性疾患の理解に貢献できると考える。