奨励賞受賞者シンポジウム「繊毛と神経機能」 JSN Distinguished Young Investigator Award Lecture Symposium: Emerging roles of primary cilia in neuronal function
S2-2-3-1 繊毛キナーゼICKは神経前駆細胞における繊毛形成とヘッジホッグシグナル伝達に重要である Ciliary kinase ICK is essential for ciliogenesis in neural progenitor cells and Hedgehog signaling ○大森義裕1,2, 茶屋太郎1, 古川貴久1,3 ○Yoshihiro Omori1,2, Taro Chaya1, Takahisa Furukawa1,3 大阪大学蛋白質研究所分子発生学研究室1, JST,さきがけ2 Institute for Protein Research, Univ Osaka, Osaka1, JST, PRESTO2, JST, CREST3 Evolutionally conserved ciliary MAP kinases (CMAPKs) have been known to negatively regulate ciliary length. CMAPK mutant animals exhibit elongated primary cilia. ICK is a broadly expressed CMAPK in mice and humans, however, its biological function is unclear. Here we analyzed mouse ICK function and found an unexpected positive role for ICK in cilia formation at developmental stages. ICK-/- mice exhibit neonatal lethality, polydactyly, hydrocephalus, and a developmental defect in the olfactory bulb. ICK absence in the brain reduced neuronal progenitor cell proliferation and produced hypoplasia of the cerebellum and hippocampus. Numbers of the cilia in neuronal progenitor cells, but not in mature neurons, markedly decreased in the ICK-/- retina and brain. We found that Hedgehog signaling components are aberrantly present in the ICK-/- MEF cilia without Shh pathway stimulation. In ICK-/- MEFs, IFT88, a member of the IFT complex B components, accumulated at ciliary tips. These results revealed that ICK is essential for ciliogenesis, Hedgehog signal transduction, and ciliary protein transport including proper localization of Hedgehog signal components in the cilia.	S2-2-3-2 グリア細胞における一次繊毛の多彩な機能 Multiple functions of glial primary cilia ○竹田扇1 ○Sen Takeda1 山梨大学大学院医学工学総合研究部解剖学講座細胞生物学教室1 Dept Anat Cell Biol, Univ of Yamanashi, Chuo1 Neuronal functions do not depend on solely neurons, but glial cells play crucial roles by supporting and modulating the activity of neurons. Glial cells also possess the primary cilia, which are regarded as a cellular antenna for sensing the extracellular milieu to cope with the incessantly changing environment. In this presentation, we focus on the primary cilia in three different types of glial cells and discuss the emerging roles of glial primary cilia. Choroid plexus epithelial cells (CPECs) are glial cells in the brain ventricles and produce the cerebrospinal fluid (CSF). Interestingly, these cells possess atypical multiple cilia. Deciliation of CPEC facilitated the fluid transcytosis, the results implying the multiple cilia as a repressor of CSF production. We identified a receptor for neuropeptide FF (NPFF) on the primary cilia, whose activation by NPFF decreased the CSF production. Astrocytes constitute major glial population in the central nervous system and support neurons by giving structural reinforcement as well as supplying the nutrients. Astrocytes possess a typical primary cilium that expresses the signaling molecules for hedgehog (Hh). Under serum deprivation, astrocytes succumb to stress and go to cell death. However, upon administration of SAG, a potent activator of Hh signaling pathway, the cell survival ratio was improved significantly, the result suggesting important roles of glial primary cilia in cell survival. Schwann cells are glial cells in the peripheral nervous system and engage in the myelination of axons. While they also have primary cilium, on which signaling molecules for Hh are expressed, these cells did not respond to sonic hedgehog (Shh). Very intriguingly, they responded to only Desert hedgehog (Dhh) to facilitate the myelination. Moreover, the expression of primary cilia proper is temporally regulated.
S2-2-3-3 ニューロンの1次繊毛上のGタンパク共役型受容体 G protein-coupled receptors at primary cilia of neurons ○三好耕1 ○Ko Miyoshi1 岡山大学大学院医歯薬学総合研究か脳神経制御学講座神経情報学1 Dept of Brain Sci, Grad Sch of Med Dent Pharm Sci, Okayama Univ, Okayama, Japan1 Almost all vertebrate cells have an immotile primary cilium that singly extends like an antenna into the environment surrounding the cell and transduces sensory stimuli to the cell body. In the rodent brain, each neuron has a solitary primary cilium for nearly all regions, although the biological roles played by the neuronal primary cilia remain unclear. In the mouse brain, adenylyl cyclase 3 and certain G protein-coupled receptors (GPCRs) (somatostatin receptor type 3, serotonin receptor type 6 and melanin-concentrating hormone receptor type 1) have been found to be co-localized in primary cilia of neuronal cells. It might then be possible that a G protein/cAMP signaling cascade in neuronal primary cilia transduces the extracellular chemical stimuli to the neuronal cell body. An Ax(S/A)xQ motif in the third intracellular loop of these GPCRs is proposed to be a ciliary targeting sequence (CTS). The mechanisms underlying preferential localization of specific GPCRs to the ciliary membrane have been recently elucidated. Recognition of CTS by the BBSome, a complex consisting of the Bardet-Biedl syndrome (BBS) proteins, has been shown to mediate targeting of somatostatin receptor type 3 to the primary cilium. Tubby family proteins that bind membrane phosphoinositides have been demonstrated to promote GPCR trafficking into the primary cilium. A membrane diffusion barrier at the base of the primary cilium is thought to segregate selected proteins in the ciliary membrane. We have characterized ciliary localization of several GPCRs including dopamine receptors in inner medullary collecting duct (IMCD) cells, cultured neurons and the brain of mice. Dopamine receptors type 1-5 have been heterogeneously targeted to the primary cilium.	S2-2-3-4 Primary cilia in the migration and function of adult-born granule cells ○Soyoung Rhee1 Department of Neurobiology and Behavior, State University of New York1 Granule neurons are continuously generated in the adult hippocampus. Primary cilia have been shown not only important to the generation but also integration of these newborn cells. In this presentation, I will first briefly talk about the recent updates on 'primary cilia-neuronal migration and behaviors'. Next, I will present you our recent findings in these aspects. In the end, I will introduce some potential signaling pathways through primary cilia which may underlie these findings.

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