若手道場
突起伸展と回路網形成 |
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| 7月7日（金） 16:00-17:00 Room E
2W④-1
神経回路形成因子LOTUSの発現はBDNFとIL-6によって促進される
Expression of LOTUS, a neural circuit formation factor, is promoted by BDNF and IL-6
松林 潤平1, 川口 祐生1,2, 山口 佳純1, 西田 遼平1, 竹居 光太郎1,2
1. 横浜市立大学大学院 生命医科学研究科 生体機能医科学研究室, 2. 横浜市立大学大学院 医学研究科 臓器再生医学教室
Junpei Matsubayashi1, Yuki Kawaguchi1,2, Kasumi Yamaguchi1, Ryohei Nishida1, Kohtaro Takei1,2
1. Molecular Medical Bioscience Laboratory, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan, 2. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
The adult mammalian CNS neurons fail to regenerate after injury. Lateral olfactory tract usher substance (LOTUS) contributes to axonal tract formation in the developing brain and axon regrowth in the adult brain as an endogenous NgR1 antagonist. LOTUS is expected to be useful for future therapy of CNS damage by inhibiting NgR1 functions. However, it needs to be better understood how LOTUS expression is regulated. Herein, we found that BDNF and IL-6 increase LOTUS expression in hippocampal neurons. Exogenous application of BDNF increased LOTUS expression at both mRNA and protein levels in cultured hippocampal neurons. Pharmacological analysis and siRNA knockdown revealed that BDNF increases LOTUS expression through the TrkB and its downstream signalings, such as MAPK and PI3K pathways.
Furthermore, neurite outgrowth assay in cultured hippocampal neurons revealed that BDNF-induced LOTUS expression promoted neurite outgrowth by antagonism for NgR1. Moreover, we also found that IL-6 increased LOTUS expression in cultured hippocampal neurons, similar to BDNF. The intraperitoneal administration of IL-6 increased LOTUS expression in the hippocampus of aging mice and enhanced memory.
These findings suggest that BDNF and IL-6 may act as positive regulators of LOTUS expression and synergistically affect axon regrowth and memory formation through the upregulation of LOTUS expression. | | 7月7日（金） 16:00-17:00 Room E
2W④-2
BDNFは大脳皮質ニューロンにおいてSRF転写コアクチベーターMRTFBをリン酸化し、転写を制御する
BDNF induces phosphorylation of the SRF transcriptional coactivator MRTFB and SRF-mediated transcription in neurons
榊原 信太郎1, 佐々木 繁2, 伊原 大輔2, 櫻井 宏明3, 田渕 明子2
1. 富山大学 大学院医薬理工学環認知・情動脳科学プログラム 分子神経生物学, 2. 富山大学 学術研究部薬学・和漢系 分子神経生物学, 3. 富山大学 学術研究部薬学・和漢系 がん細胞生物学
Shintaro Sakakibara1, Shigeru Sasaki2, Daisuke Ihara2, Hiroaki Sakurai3, Akiko Tabuchi2
1. Lab. Mol.Neurobiol.,Grad.Sch.,Pharm-Med. Sci.,Grad. Prog.Cognitive and Emotional Neurosci., Univ. of TOYAMA, Toyama, Japan, 2. Lab. Mol.Neurobiol., Fac. Pharm. Sci., Univ. of TOYAMA, Toyama, Japan, 3. Lab. Cancer Cell Biol., Fac. Pharm. Sci., Univ. of TOYAMA, Toyama, Japan
Neural plasticity, which is a molecular basis of higher brain function, is associated with gene expression and morphological changes. We focus on the myocardin-related transcription factor (MRTF) molecules, consist of MRTFA and MRTFB, which control the expression of immediate early genes (IEGs) and cytoskeletal genes through interacting with SRF and morphological alteration. Our previous study revealed that BDNF induces an IEG, activity-regulated cytoskeleton-associated protein (Arc) via MRTFB. In this study, we investigated how brain-derived neurotrophic factor (BDNF) signaling activates MRTFB in cortical neurons. We found that phosphorylation of MRTFB was induced by stimulation of cortical neurons with BDNF. Although BDNF activates ERK/MAPK, PI3K-Akt and PLC pathways via TrkB, ERK/MAPK is found to be the main pathway for BDNF-mediated phosphorylation of MRTFB. In addition, the 913th serine residue of MRTFB tends to be involved in BDNF-induced SRF-mediated transcriptional activity in cortical neurons. Ongoing studies are aimed at identifying the phosphorylation sites of MRTFB involved in the induction of SRF-target genes such as Arc and investigating the function in neuronal morphology. | | 7月7日（金） 16:00-17:00 Room E
2W④-3
Novel molecular mechanisms underlying axon collateral formation
Jiaxuan Li1,2, 安村 美里2, 谷口 学2, 佐藤 真1,2,3
1. 大阪大学生命機能研究科, 2. 大阪大学医学系研究科神経機能形態学, 3. 大阪大学連合小児発逹学研究科
Jiaxuan Li1,2, Misato Yasumura2, Manabu Taniguchi2, Makoto Sato1,2,3
1. Grad Sch of Front Bio, Osaka Univ, Osaka, Japan, 2. Dept Anat & Neurosci, Grad Sch Med, Osaka Univ, Osaka, Japan, 3. Div of Dev Neurosci, United Grad Sch of Child Dev, Osaka Univ, Osaka, Japan
The corticospinal tract is a critical neural pathway that plays a vital role in motor function. During the development of the corticospinal tract, axon collaterals protrude from their main shaft toward the pons. Despite its significance, the molecular mechanisms underlying the development of axon collaterals during corticospinal tract formation remain poorly understood. We previously showed that axon collateral formation toward the pons was suppressed by the knockdown of specific receptor protein tyrosine phosphatase (RPTP). To gain a deeper understanding of the RPTP family's role in axon collateral formation, we conducted further knockdown experiments on various members of the RPTP family. Unexpectedly, the knockdown of one RPTP (tentatively called RPTP1) gave us the opposite effects: its knockdown resulted in an increase in the number of axon branches. To elucidate the mechanisms underlying RPTP1's role in axon collateral arborization, we studied the interaction between RPTP1 and molecules which are already demonstrated to be involved in axon growth. RPTP1 negatively regulated axon collateral formation by dephosphorylating Ephrin-type receptor. Our findings indicate the importance of RPTP1-Ephrin axis in regulating axon collateral formation.(COI: No) | | 7月7日（金） 16:00-17:00 Room E
2W④-4
Apolipoprotein B-100に誘導された瘢痕化による脊髄損傷後の機能回復阻害作用
Circulating apolipoprotein B-100 exacerbates spinal cord injury by inducing the pericyte-derived scarring
米津 好乃1,2, 田辺 章悟1, 三澤 日出巳2, 村松 里衣子1
1. 国立精神・神経医療研究センター 神経研究所 神経薬理研究部, 2. 慶應義塾大学大学院 薬学研究科 薬理学講座
Yoshino Yonezu1,2, Shogo Tanabe1, Hidemi Misawa2, Rieko Muramatsu1
1. Dept. of Mol. Pharmacol., Natl. Inst. of Neurosci., Natl. Ctr. of Neurology and Psychiatry, 2. Dept. of Pharmacol., Grad. Sch. of Pharmaceut. Sci., Keio Univ.
Spinal cord injury (SCI) is a devastating event that results in a permanent neurologic deficit related to the failure of neuronal network reconstruction. After SCI, type A pericytes proliferate around the lesion and contribute to the fibrotic scar formation, which has been considered one of the primary causes of regeneration impairment. Therefore, inhibition of pericyte proliferation may be useful to promote neuronal network regeneration after SCI; however, the molecular mechanisms underlying the pericyte proliferation in response to the damage remain unclear. In this study, we employed a CRISPR-Cas9 knockout screen and identified circulating apolipoprotein B-100 (ApoB-100) as a potential regulator in pericyte proliferation mediated through ApoB-100/ low density lipoprotein receptor (LDLR) signaling. We found that ApoB-100 knockout mice exhibited a reduction of pericyte-derived scarring and displayed improved restoration of motor function after SCI. Similarly, inhibition of LDLR expression in type A pericytes of injured mice also reduced pericyte-derived scar formation and promoted the functional recovery. Taken together, circulating ApoB-100 exerts a crucial role in pericyte proliferation via LDLR, blocking ApoB-100 or its interaction with LDLR may provide potential therapeutic benefits to improve outcomes after SCI. | |
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