Functional analysis of a melanin-concentrating hormone receptor that localizes to primary cilia

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14742
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44040:Morphology and anatomical structure-related
• Research Institution: Hiroshima University
• Principal Investigator: Kobayashi Yuki 広島大学, 統合生命科学研究科(総), 助教 (80736421)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 一次繊毛 / メラニン凝集ホルモン / MCHR1 / 海馬スライス培養 / 海馬初代培養 / iPS細胞

Outline of Final Research Achievements

Melanin-concentrating hormone (MCH) plays a role in various physiological functions such as feeding, emotion, and sleep via interactions with MCH receptor 1 (MCHR1), which is a membrane receptor. Recently, some GPCRs, including MCHR1, have been shown to localize to the membrane of primary cilia instead of the cell membrane. Previously, we have found that MCHR1-positive cilia are shortened by MCH stimulation in hRPE1 cells. In this study, we treated hPRE1 cells with inhibitors, siRNAs, and CRISPR-Cas9 and performed western blot and RNAseq analyses to determine signals and mediator molecules that are involved in ciliary shortening. We have also demonstrated that the MCH-MCHR1 system causes ciliary shortening in organotypic rat hippocampal slice cultures, rat primary hippocampal dissociated cultures, and hiPSC-derived cortical neurons via a similar mechanism. In conclusion, these results suggest that ciliary MCHR1 play a role in ciliary shortening.

Free Research Field

神経化学

Academic Significance and Societal Importance of the Research Achievements

GPCRは、細胞膜上に局在する事を前提に研究が進められてきた。近年、MCHR1を含む幾つかのGPCRが、細胞膜ではなく、肥満を含む様々な疾患に関与する一次繊毛というオルガネラの膜上に発現することが報告された。さらに、MCHを介してMCHR1陽性一次繊毛が短くなることを培養細胞系にて明らかにしている。本研究では、培養系（培養細胞、海馬初代培養、海馬器官培養等）および個体の脳を用いて、MCH-MCHR1を介した繊毛縮退の普遍性と縮退の分子機構の解明を試みた。本成果は、1次繊毛という「場」を起点とするGPCRシグナルとそれに続く生理作用を制御する神経回路の解明に繋がる新たな道を拓く可能性がある。