突起伸展2 Neurite Growth 2
O1-6-4-1 損傷後視神経の視覚中枢回路再建と視機能回復 Reinnervation of visual system and recovery of visual responses in adult mice by optic nerve regeneration ○郡山恵樹1,3, 栗本拓治2,3 ○Yoshiki Koriyama1,3, Takuji Kurimoto2,3, Silmara DeLima3, Larry Benowitz3 金沢大学　医薬保健研究域　医学系 脳情報分子学1, 大阪医科大学、眼科2, ハーバード大・医・眼科/神経外科3 Dept of Mol Neurobiol, Grd Sch of Med, Kanazawa Univ, Kanazawa1, Dept of Ophthalmol Osaka Med Col, Osaka2, Dept of Surgery and Ophthalmol in Neurosci Harvard Med Sch, USA3 Adult retinal ganglion cells (RGCs) do not regenerate axons after optic nerve injury. Recent studies have identified molecular pathways able to allow partial regeneration of the damaged RGC axons in mature rodents. It is still unknown whether regrowing optic axons can enter visual center in large numbers, innervate to correct target areas and restore vision. We investigated these questions using the manipulations that synergistically increase regeneration far above the level induced by any one alone. Oncomodulin(Ocm), a calcium binding protein that is secreted from activated macrophages, is associated with the inflammation-induced axonal regeneration. This regeneration is further enhanced by elevating intracellular cAMP. Studies were carried out in mice with a conditional deletion of the gene encoding PTEN, a phosphatase and tensin homolog that suppresses signaling through the PI3K/Akt pathway. In one group of mice, the pten gene was deleted in RGCs by injecting adeno-associated virus expressing Cre recombinase into the eye. Another group of mice were treated similarly except for receiving intraocular injections of AAV2 expressing GFP. Ten weeks after the initial surgery, mice receiving the 3-ways' treatment (Ocm+cAMP+PTEN deletion) showed extensive axon regeneration along the entire length of the optic nerve, across the optic chiasm and to the optic tract, selectively innervating the visual target areas. The regeneration significantly restored basic visual responses. Mice receiving the 3-ways' treatment showed improvements in the optomotor response and depth avoidance tests. These results demonstrate the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.	O1-6-4-2 プロトカドヘリン17は接着依存的に扁桃体の軸索伸長を支える Protocadherin-17 sustains amygdala axon extension by contact-dependent mechanisms ○林周一1, 竹市雅俊1 ○Shuichi Hayashi1, Masatoshi Takeichi1 理化学研究所　発生再生科学総合研究センター1 RIKEN Center for Developmental Biology (CDB), Kobe1 Regulation of axon extension is essential for neuronal wiring. Axons often extend toward the targets forming a bundle, within which they directly contact to each other. It is poorly understood how their contacts are involved in the regulation of axon extension. Non-clustered protocadherins are a group of transmembrane proteins that belongs to the cadherin superfamily. We analyzed the function of one of these protocadherins, protocadherin-17 (Pcdh17), and found that Pcdh17 is localized along a subpopulation of amygdala axons projecting towards the bed nucleus of the stria terminalis (BST) in embryonic and early postnatal mice. These amygdala axons were significantly reduced in PCDH17 mutant mice, suggesting that Pcdh17 is required for their extension. Pcdh17 interacted with the Nck-associated protein-1 (Nap1), a molecule essential for lamellipodia formation and cell migration. In cultured cells, Pcdh17 localized at cell-cell contacts due to its homophilic binding nature, and recruited Nap1 to the contact sites. This process resulted in the promotion of cell motility through the activation of Arp2/3-dependent actin polymerization. In growing axons from amygdala explants, Pcdh17 was localized at contacts between a growth cone and other axons. Live imaging revealed that the growth cone motility is inhibited at axon-axon contact sites in PCDH17 mutants. These results suggest that Pcdh17-dependent contacts between axons promote their extension, and may contribute to neuronal type-specific promotion of axon growth.
O1-6-4-3 セマフォリン3Aによる逆行性軸索輸送はAMPA受容体サブユニット・GluA2の樹状突起への局在化を介し樹状突起分枝形成を調節する A retrograde axonal transport elicited by Semaphorin3A regulates dendritic arborization through localization of AMPA receptor subunit GluA2 in dendrites ○山下直也1, 五嶋良郎1 ○Naoya Yamashita1, Yoshio Goshima1 横浜市立大学医学部分子薬理神経生物学1 Dept. Mol. Pharmacol. & Neurobiol., Yokohama City Univ, Yokohama1 Neurons are compartmentalized into two molecularly and functionally distinct domains, axon and dendrites. These subcellular compartments need to communicate with each other. For example, signals received in distal axon travel long distances to reach the cell body and/or dendrites. We here demonstrate that Semaphorin3A (Sema3A), a secreted factor that navigates axons and dendrites, induces a retrograde axonal transport signaling, which regulates AMPA receptor subunit GluA2 localization in dendrites. In cultured hippocampal neurons at axon outgrowth stage, Sema3A enhances immunofluorescence levels of GluA2 in dendrites. The site of action of Sema3A is restricted at the axonal growth cone and the signaling elicited in the axonal growth cone is propagated toward the cell body by dynein-dependent retrograde axonal transport. Sema3A induces retrograde axonal transport of its own. Immunofluorescence level of PlexinA4, a receptor component for Sema3A, is increased by Sema3A in dendrites whereas decreased in distal axon, suggesting that Sema3A and its receptors are retrogradely transported from distal axon to dendrites. PlexinA4 interacts with GluA2 at the immunoglobulin like, Plexins, transcription factors domain (PlexA-IPT). Application of PlexA-IPT suppresses dendritic localization of GluA2 and exhibits proximal bifurcation phenotype of CA1 hippocampal pyramidal neurons, a similar phenotype seen in sema3A knockout mice. Knock down of GluA2 suppresses Sema3A-induced dendritic branch formation. Our results identify a novel control mechanism of the glutamate receptors and provide evidence for a Sema3A-induced retrograde signaling which regulates dendritic arborization through localization of GluA2 in dendrites.	O1-6-4-4 微小管集積因子であるNeuronnavigatorのホモログであるSickieは、非古典的Rac/Slingshot/Cofilin経路を介したアクチン骨格制御を通してショウジョウバエキノコ体の神経軸索伸長を制御する Sickie, a mammalian MAP Nav2 homolog, regulates axonal growth of Drosophila Mushroom Body neurons via Rac/Slingshot/Cofilin-dependent F-actin regulation ○阿部崇志1, 山崎大介1, 村上智史1, 前山有子1, 多羽田哲也1 ○Takashi Abe1, Daisuke Yamazaki1, Satoshi Murakami1, Yuko Maeyama1, Tetsuya Tabata1 東京大学 分子細胞生物学研究所 神経生物学分野1 Dept Neurosci, IMCB, Univ of Tokyo, Tokyo1 Axonal growth is basic but fundamental process for functional network formation. Drosophila Mushroom Body (MB), the third-order interneurons crucial for olfactory memory, has been studied as a model for neuronal development. Previous studies have shown that RacGTPase (Rac) signaling cascade regulates axonal growth via downstream Cofilin pathways. Cofilin is a critical regulator of F-actin turnover, and its activity is positively regulated by Slingshot and negatively by LIMK. Consistently, loss of function of Cofilin and Slingshot, and gain of function of canonical Rac/Pak/LIMK signaling components result in axonal growth defects. Interestingly, several genetic evidences have suggested that Rac has bidirectional activities, and the existence of novel factors that transduce non-canonical Rac activity to facilitate MB axon growth has been predicted. However, it remained elusive how such non-canonical Rac activity eventually contributes to the axonal growth. Moreover, there are only a few reports that demonstrate the endogenous changes of Cofilin activities and subsequent F-actin regulation in vivo. To address these issues, we conducted enhancer-trap screening to identify key molecules for MB development. We found the prominent expression of Sickie, a human Microtubule Associated Protein Neuron-navigator homolog, in F-actin-rich developing axons. We found that Sickie is required for MB axon growth cell-autonomously, and shows synergistic interactions with the RacGTPase/Cofilin signaling components. Several epistasis analyses suggest that Sickie mediates the Pak-independent Rac activity and positively regulates the MB axonal growth through the Slingshot-dependent F-actin regulation. Based on the distinct morphological phenotypes and simultaneous detections of F-actin/phospho-Cofilin expression patterns, we propose that Sickie regulates MB axon growth by providing both signal and cytoskeletal links in RacGTPase/Cofilin pathway and Actin/Microtubule cytoskeleton.

上部に戻る

前に戻る