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Abstract Myelin sheath abnormality is the cause of various neurodegenerative diseases (NDDs). G-proteins and their coupled receptors (GPCRs) play the important roles in myelination. Gnao1, encoding the major Gα protein (Gαo) in mammalian nerve system, is required for normal motor function. Here, we show that Gnao1 restricted to Schwann cell (SCs) lineage, but not neurons, negatively regulate SC differentiation, myelination, as well as re-myelination in peripheral nervous system (PNS). Mice lacking Gnao1 expression in SCs exhibit faster re-myelination and motor function recovery after nerve injury. Conversely, mice with Gnao1 overexpression in SCs display the insufficient myelinating capacity and delayed re-myelination. In vitro, Gnao1 deletion in SCs promotes SC differentiation. We found that Gnao1 knockdown in SCs resulting in the elevation of cAMP content and the activation of PI3K/AKT pathway, both associated with SC differentiation. The analysis of RNA sequencing data further evidenced that Gnao1 deletion cause the increased expression of myelin-related molecules and activation of regulatory pathways. Taken together, our data indicate that Gnao1 negatively regulated SC differentiation by reducing cAMP level and inhibiting PI3K-AKT cascade activation, identifying a novel drug target for the treatment of demyelinating diseases.

Abstract Background Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. Methods By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. Results Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. Conclusion Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Abstract Background Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI. Methods PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents. Results MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K–AKT–mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice. Conclusions Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

Table of contents O1 Changes in peripheral refraction associated with decreased ocular axial growth rate in marmosets Alexandra Benavente-Perez, Ann Nour, Tobin Ansel, Kathleen Abarr, Luying Yan, Keisha Roden, David Troilo O2 PPARα activation suppresses myopia development by increasing scleral collagen synthesis--a new drug target to suppress myopia development Chanyi Lu, Miaozhen Pan, Min Zheng, Jia Qu, Xiangtian Zhou O3 Evidence and possibilities for local ocular growth regulating signal pathways Christine F Wildsoet O4 Myopia researches at Eye Hospital of Wenzhou Medical University Fan Lu, Xiangtian Zhou, Jie Chen, Jinhua Bao, Liang Hu, Qinmei Wang, Zibing Jin, Jia Qu O5 Color, temporal contrast and myopia Frances Rucker, Stephanie Britton, Stephan Hanowsky, Molly Spatcher O6 The impact of atropine usage on visual function and reading performance in myopic school children in Taiwan Hui-Ying Kuo, Ching-Hsiu Ke, I-Hsin Kuo, Chien-Chun Peng, Han-Yin Sun O7 Increased time outdoors prevents the onset of myopia: evidence from randomised clinical trials Ian G Morgan O8 Environmental risk factors and gene-environment interactions for myopia in the ALSPAC cohort Jeremy A. Guggenheim, Rupal L. Shah, Cathy Williams O9 Retinal metabolic profiling identifies declines in FP receptor-linked signaling as contributors to form-deprived myopic development in guinea pigs Jinglei Yang, Peter S. Reinach, Sen Zhang, Miaozhen Pan, Wenfeng Sun, Bo Liu, Xiangtian Zhou O10 The study of peripheral refraction in moderate and high myopes after one month of wearing orthokeratology lens Jun Jiang, Haoran Wu, Fan Lu O11 Axial length of school children around the earth’s equatorial area and factors affecting the axial length Kazuo Tsubota, Hiroko Ozawa, Hidemasa Torii, Shigemasa Takamizawa, Toshihide Kurihara, Kazuno Negishi O12 Processing of defocus in the chicken retina by retinal ganglion cells Klaus Graef, Daniel Rathbun, Frank Schaeffel O13 Blue SAD light protects against form deprivation myopia in chickens, by local signaling within the retina Ladan Ghodsi, William K. Stell O14 Contributions of ON and OFF pathways to emmetropization and form deprivation myopia in mice Machelle T. Pardue, Ranjay Chakraborty, Han na Park, Curran S. Sidhu, P. Michael Iuvone O15 Response of the human choroid to defocus Michael J Collins O16 What can RNA sequencing tell us about myopic sclera? Nethrajeith Srinvasalu, Sally A McFadden, Paul N Baird O17 Overview of dopamine, retinal function, and myopia P. Michael Iuvone O18 The eye as a "robust" optical system and myopia Pablo Artal O19 Effect of discontinuation of orthokeratology lens wear on axial elongation in children Pauline Cho, SW Cheung O20 Myopia prevention in Taiwan Pei-Chang Wu O21 Alternatives to ultraviolet light and riboflavin for in vivo crosslinking of scleral collagen Quan V. Hoang, Sally A. McFadden O22 Absence of intrinsically photosensitive retinal ganglion cells (ipRGC) alters normal refractive development in mice Ranjay Chakraborty, Duk C. Lee, Erica G. Landis, Michael A. Bergen, Curran Sidhu, Samer Hattar, P. Michael Iuvone, Richard A. Stone, Machelle T. Pardue O23 Scleral micro-RNAs in myopia development and their potential as therapeutic targets Ravi Metlapally O24 Effects of the long-wavelength filtered continuous spectrum on emmetropization in juvenile guinea pigs Ruiqin Li, Qinglin Xu, Hong Zhon, Chenglin Pan, Weizhon Lan, Xiaoning Li, Ling Chen, Zhikuan Yang O25 Ocular and environmental factors associated with eye growth in childhood Scott A. Read O26 Overview- prevention and prediction of myopia and pathologic myopia Seang-Mei Saw O27 New insights into the roles of retinal dopamine in form-deprivation myopia and refractive development in C57BL/6 mice Shi-Jun Weng, Xiao-Hua Wu, Kang-Wei Qian, Yun-Yun Li, Guo-Zhong Xu, Furong Huang, Xiangtian Zhou, Jia Qu, Xiong-Li Yang, Yong-Mei Zhong O28 The effects of the adenosine antagonist, 7-methylxanthine, on refractive development in rhesus monkeys Earl L Smith III, Baskar Arumugam, Li-Fang Hung, Lisa A. Ostrin, Klaus Trier, Monica Jong, Brien A. Holden O29 Application of SWATH™ based next generation proteomics (NGP) in studying eye growth: opportunities and challenges Thomas Chuen Lam, Bing Zuo, Samantha Shan, Sally A. McFadden, Dennis Yan-yin Tse, Jingfang Bian, King-Kit Li, Quan Liu, Chi-ho To O30 How could emmetropization make use of longitudinal chromatic aberration? Timothy J. Gawne, John T. Siegwart Jr., Alexander H. Ward, Thomas T. Norton O31 Balance effect of dopamine D1 and D2 receptor subtype activation on refraction development Xiangtian Zhou O32 BMP gene expression changes in chick rpe in response to visual manipulations Yan Zhang, Yue Liu, Carol Ho, Eileen Phan, Abraham Hang, Emily Eng, Christine Wildsoet