Studies on a novel signaling pathway that mediates postnatal body growth

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591370
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Wakayama Medical University
• Principal Investigator: SAKAGUCHI Kazushige 和歌山県立医科大学, 先端医学研究所, 教授 (60178548)
• Co-Investigator(Kenkyū-buntansha): SAWADA Takahiro 和歌山県立医科大学, 先端医学研究所, 非常勤講師 (00382325) ; FURUSHIMA Kenryo 和歌山県立医科大学, 先端医学研究所, 講師 (50392105) ; JING Xuefeng 和歌山県立医科大学, 先端医学研究所, 講師 (70316123) ; MIYAJIMA Masayasu 和歌山県立医科大学, 共同利用施設, 講師 (80137257) ; ARAI Daiki 和歌山県立医科大学, 先端医学研究所, 学内助教 (90725574) ; MIWA Hideto 和歌山県立医科大学, 医学部, 准教授 (50231626)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 体格決定 / 成長ホルモン / インスリン様成長因子 / Eph / ephrin / JAK2 / STAT / シグナル伝達

Outline of Final Research Achievements

The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the JAK2/STAT5B signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Pituitary Gh mRNA and plasma GH levels were not reduced. IGF1 injection rescued the phenotype of Epha4-KO mice. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination.

Free Research Field

分子医学