Selected Publications
March 2025 | Nature Communications
Zhang, X, Yang, C, Zhang, C, Wu, J, Zhang, X, Gao, J, Wang, X, Chan, LT, Zhou, Y, Chen Y, Ma YQ, Yung WH, Duan L, Jiang L, Wang Y, Liu K.
Abstract
Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries.
September 2024 | PNAS
Chen W, Wu J, Yang C, Li S, Liu Z, An Y, Wang XJ, Cao J, Xu J, Duan Y, Yuan X, Zhang X, Zhou Y, Ip J PK, Fu A KY, Ip NY, Yao ZP, Liu K.
Abstract
Adult central nervous system (CNS) neurons down-regulate growth programs after injury, leading to persistent regeneration failure. Coordinated lipids metabolism is required to synthesize membrane components during axon regeneration. However, lipids also function as cell signaling molecules. Whether lipid signaling contributes to axon regeneration remains unclear. In this study, we showed that lipin1 orchestrates mechanistic target of rapamycin (mTOR) and STAT3 signaling pathways to determine axon regeneration. We established an mTOR-lipin1-phosphatidic acid/lysophosphatidic acid-mTOR loop that acts as a positive feedback inhibitory signaling, contributing to the persistent suppression of CNS axon regeneration following injury. In addition, lipin1 knockdown (KD) enhances corticospinal tract (CST) sprouting after unilateral pyramidotomy and promotes CST regeneration following complete spinal cord injury (SCI). Furthermore, lipin1 KD enhances sensory axon regeneration after SCI. Overall, our research reveals that lipin1 functions as a central regulator to coordinate mTOR and STAT3 signaling pathways in the CNS neurons and highlights the potential of lipin1 as a promising therapeutic target for promoting the regeneration of motor and sensory axons after SCI.
January 2023 | Neuron
Wang X, Yang C, Wang XJ, Miao J, Chen W, Zhou Y, Xu Y, An Y, Cheng A, Ye W, Chen M, Song D, Yuan X, Wang J, Qian P, Wu AR, Zhang ZY, Liu K.
Abstract
The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal STING by cGAMP promotes axon regeneration. In contrast to the central axons, IFNγ is locally translated in the injured peripheral axons and upregulates cGAS expression in Schwann cells and infiltrating blood cells to produce cGAMP, which promotes spontaneous axon regeneration as an immunotransmitter. Our study demonstrates that injured peripheral nervous system (PNS) axons can direct the environmental innate immune response for self-repair and that the neural antiviral mechanism can be harnessed to promote axon regeneration in the central nervous system (CNS).
January 2020 | Neuron
Yang C, Wang X, Wang JY, Wang XJ, Chen W, Lu N, Siniossoglou S, Yao ZP, Liu K.
Abstract
How adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. Regrowth induced by lipin1 depletion required TG hydrolysis and PL synthesis. Decreasing TG synthesis by deleting neuronal diglyceride acyltransferases (DGATs) and enhancing PL synthesis through the Kennedy pathway promoted axon regeneration. In addition, peripheral neurons adopted this mechanism for their spontaneous axon regeneration. Our study reveals a critical role of lipin1 and DGATs as intrinsic regulators of glycerolipid metabolism in neurons and indicates that directing neuronal lipid synthesis away from TG synthesis and toward PL synthesis may promote axon regeneration.
February 2016 | PNAS
Li S, Yang C, Zhang L, Gao X, Wang X, Liu W, Wang Y, Jiang S, Wong YH, Zhang Y, Liu K.
Abstract
Cell-type–specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.
July 2015 | Journal of Neuroscience
Du K, Zheng S, Zhang Q, Li S, Gao X, Wang J, Jiang L, Liu K.
Abstract
Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). This study shows that Pten deletion in the adult mouse cortex enhances compensatory sprouting of uninjured CST axons. Furthermore, forced upregulation of mammalian target of rapamycin (mTOR) initiated either 1 month or 1 year after injury promoted regeneration of CST axons. Our results indicate that both developmental and injury-induced mTOR downregulation in corticospinal motor neurons can be reversed in adults. Modulating neuronal mTOR activity is a potential strategy for axon regeneration after chronic SCI.
September 2010 | Nature Neuroscience
Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z.
Abstract
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
November 2008 | Science
Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, He Z.
Abstract
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
By Years
2025
Chengle Zhang , Kai Liu
Neuron 113 (5), 643-645 (Mar 2025)
Xin Zhang, Chao Yang, Chengle Zhang, Junqiang Wu, Xiang Zhang, Jiayang Gao, Xuejie Wang, Leung Ting Chan, Yiren Zhou, Yujun Chen, Sindy Sing Ting Tam, Shuhang Chen, Yuqian Ma, Wing-Ho Yung, Liting Duan, Liwen Jiang, Yiwen Wang, Kai Liu
Nature Communications 16 (1), 2174 (Mar 2025)
2024
Yue Li, Chao Yang, Shiyu Fang, Yiren Zhou, Manjia Li, Zewei Liu, Xin Zhang, Liting Duan, Kai Liu, Fei Sun
Advanced Materials, e241395 (Dec 2024)
Wanjie Wu, Yingzhu He, Yujun Chen, Yiming Fu, Sicong He, Kai Liu, Jianan Y Qu
Nature communications 15 (1), 8837 (Oct 2024)
Yubing Li, Yipeng Zhao, Yaojun He, Fang Liu, Lu Xia, Kai Liu, Mingjie Zhang, Keyu Chen
Journal of Biological Chemistry 300 (10), 107762 (Oct 2024)
Weitao Chen, Junqiang Wu, Chao Yang, Suying Li, Zhewei Liu, Yongyan An, Xuejie Wang, Jiaming Cao, Jiahui Xu, Yangyang Duan, Xue Yuan, Xin Zhang, Yiren Zhou, Jacque Pak Kan Ip, Amy KY Fu, Nancy Y Ip, Zhongping Yao, Kai Liu
Proceedings of the National Academy of Sciences 121 (39), e2404395121 (Sep 2024)
Yutong Song, Zhihao Zhao, Linyu Xu, Peiyuan Huang, Jiayang Gao, Jingxuan Li, Xuejie Wang, Yiren Zhou, Jinhui Wang, Wenting Zhao, Likun Wang, Chaogu Zheng, Bo Gao, Liwen Jiang, Kai Liu, Yusong Guo, Xiaoqiang Yao, Liting Duan
Developmental Cell 59 (11), 1396-1409. e5 (Jun2024)
2023
Xu Wang, Chao Yang, Xuejie Wang, Jinmin Miao, Weitao Chen, Yiren Zhou, Ying Xu, Yongyan An, Aifang Cheng, Wenkang Ye, Mengxian Chen, Dong Song, Xue Yuan, Jiguang Wang, Peiyuan Qian, Angela Ruohao Wu, Zhong-Yin Zhang, Kai Liu
Neuron 111 (2), 236-255. e7 (Jan 2023)
2022
%20.jpg)
Wanjie Wu, Sicong He, Yujun Chen, Congping Chen, Yiming Fu, Kai Liu, Jianan Y Qu
IEEE Journal of Selected Topics in Quantum Electronics 29 (4: Biophotonics) 1-13 (Dec 2022)
RSK1 promotes mammalian axon regeneration by inducing the synthesis of regeneration-related proteins
Susu Mao, Yuanyuan Chen, Wei Feng, Songlin Zhou, Chunyi Jiang, Junjie Zhang, Xiaohong Liu, Tianmei Qian, Kai Liu, Yaxian Wang, Chun Yao, Xiaosong Gu, Bin Yu
PLoS Biology 20 (6), e3001653 (Jun 2022)
Wanjie Wu, Sicong He, Junqiang Wu, Congping Chen, Xuesong Li, Kai Liu, Jianan Y Qu
Nature communications 13 (1), 1959 (Apr 2022)
2021
Ming-Yu Wu, Alex YH Wong, Jong-Kai Leung, Chuen Kam, Kenneth Lap-Kei Wu, Ying-Shing Chan, Kai Liu, Nancy Y Ip, Sijie Chen
Proceedings of the National Academy of Sciences 118 (45), e2106143118 (Nov 2021)
2020
Bojing Jiang, Xiaotian Liu, Chao Yang, Zhongguang Yang, Jiren Luo, Songzi Kou, Kai Liu, Fei Sun
Science advances 6 (41), eabc4824 (Oct 2020)
Zhongya Qin, Sicong He, Chao Yang, Jasmine Sum-Yee Yung, Congping Chen, Christopher Kai-Shun Leung, Kai Liu, Jianan Y Qu
Light: Science & Applications 9 (1), 79 (May 2020)
.jpg)
Chao Yang, Xu Wang, Jianying Wang, Xuejie Wang, Weitao Chen, Na Lu, Symeon Siniossoglou, Zhongping Yao, Kai Liu
Neuron 105 (2), 276-292. e5 (Jan 2020)
2019
Haiqiong Wang, Xuejie Wang, Kai Zhang, Qingyao Wang, Xu Cao, Zhao Wang, Shuang Zhang, Ang Li, Kai Liu, Yanshan Fang
Science Advances 5 (2), eaav4971 (Feb 2019)
2018
Gang Wang, Han Zhu, Chenghao Situ, Lifang Han, Youqian Yu, Tom H Cheung, Kai Liu, Zhenguo Wu
The EMBO journal 37 (8), e98239 (Apr 2018)
Xiaotian Liu, Xin Yang, Zhongguang Yang, Jiren Luo, Xiaozhen Tian, Kai Liu, Songzi Kou, Fei Sun
ACS Applied Nano Materials 1 (4), 1579-1585 (Mar 2018)
Hongyun Huang, Wise Young, Lin Chen, Shiqing Feng, Ziad M Al Zoubi, Hari Shanker Sharma, (…) Kai Liu, Hamid Mobasheri, Seiji Ohtori, Hiroyuki Tanaka, Fabin Han, Yaping Feng, Shaocheng Zhang, Yingjie Lu, Zhicheng Zhang, Yaojian Rao, Zhouping Tang, Haitao Xi, Liang Wu, Shunji Shen, Mengzhou Xue, Guanghong Xiang, Xiaoling Guo, Xiaofeng Yang, Yujun Hao, Yong Hu, Jinfeng Li, Qiang Ao, Bin Wang, Zhiwen Zhang, Ming Lu, Tong L
Cell transplantation 27 (2), 310-324 (Feb 2018)
.jpg)
Yi-Lan Weng, Xu Wang, Ran An, Jessica Cassin, Caroline Vissers, Yuanyuan Liu, Yajing Liu, Tianlei Xu, Xinyuan Wang, Samuel Zheng Hao Wong, Jessica Joseph, Louis C Dore, Qiang Dong, Wei Zheng, Peng Jin, Hao Wu, Bin Shen, Xiaoxi Zhuang, Chuan He, Kai Liu, Hongjun Song, Guo-li Ming
Neuron 97 (2), 313-325. e6 (Jan 2018)
Wilson Pak-Kin Lou, Alvaro Mateos, Marta Koch, Stefan Klussman, Chao Yang, Na Lu, Sachin Kumar, Stefanie Limpert, Manuel Göpferich, Marlen Zschaetzsch, Christopher Sliwinski, Marc Kenzelmann, Matthias Seedorf, Carlos Maillo, Elena Senis, Dirk Grimm, Radhika Puttagunta, Raul Mendez, Kai Liu, Bassem A Hassan, Ana Martin-Villalba
Frontiers in Molecular Neuroscience 10, 445 (Jan 2018)
2017
Wenbao Hu, Xiaojie Yu, Zhengzhao Liu, Ying Sun, Xibing Chen, Xin Yang, Xiaofen Li, Wai Kwan Lam, Yuanyuan Duan, Xu Cao, Hermann Steller, Kai Liu, Pingbo Huang
Elife 6, e28021 (Jun 2017)
2016
Weitao Chen, Na Lu, Yue Ding, Yuan Wang, Leung Ting Chan, Xu Wang, Xin Gao, Songshan Jiang, Kai Liu
Eneuro 3 (6) (Nov 2016)
Rafer Willenberg, Katherine Zukor, Kai Liu, Zhigang He, Oswald Steward
Journal of Comparative Neurology 524 (13), 2654-2676 (Sep 2016)
Menglong Zeng, Yuan Shang, Tingfeng Guo, Qinghai He, Wing-Ho Yung, Kai Liu, Mingjie Zhang
Proceedings of the National Academy of Sciences 113 (22), E3081-E3090 (May 2016)
Songshan Li, Chao Yang, Li Zhang, Xin Gao, Xuejie Wang, Wen Liu, Yuqi Wang, Songshan Jiang, Yung Hou Wong, Yifeng Zhang, Kai Liu
Proceedings of the National Academy of Sciences 113 (7), 1937-1942 (Feb 2016)
%2C%20.jpeg)
Jennifer Wei Huen Shum, Kai Liu, Kwok-fai So
Neural regeneration research 11 (1), 32-36 (Jan 2016)
2015
.jpg)
Kaimeng Du, Susu Zheng, Qian Zhang, Songshan Li, Xin Gao, Juan Wang, Liwen Jiang, Kai Liu
Journal of Neuroscience 35 (26), 9754-9763 (Jul 2015)
%2C%20.jpg)
Cédric G Geoffroy, Ariana O Lorenzana, Jeffrey P Kwan, Kyle Lin, Omeed Ghassemi, Andrew Ma, Nuo Xu, Daniel Creger, Kai Liu, Zhigang He, Binhai Zheng
Journal of Neuroscience 35 (16), 6413-6428 (Apr 2015)
Songshan Li, Qinghai He, Hao Wang, Xuming Tang, Kam Wing Ho, Xin Gao, Qian Zhang, Yang Shen, Annie Cheung, Francis Wong, Yung Hou Wong, Nancy Y Ip, Liwen Jiang, Wing Ho Yung, Kai Liu
Neurobiology of disease 73, 366-376 (Jan 2015)
2014
.jpg)
Wei-Qun Fang, Wei-Wei Chen, Liwen Jiang, Kai Liu, Wing-Ho Yung, Amy KY Fu, Nancy Y Ip
Cell reports 9 (5), 1635-1643 (Dec 2014)
2011
Kai Liu, Andrea Tedeschi, Kevin Kyungsuk Park, Zhigang He
Annual review of neuroscience 34 (1), 131-152 (Jul 2011)
Joanne Babiarz, Noriko Kane-Goldsmith, Sayantani Basak, Kai Liu, Wise Young, Martin Grumet
Experimental neurology 229 (1), 72-79 (May 2011)
2010
%2C.png)
Kai Liu, Yi Lu, Jae K Lee, Ramsey Samara, Rafer Willenberg, Ilse Sears-Kraxberger, Andrea Tedeschi, Kevin Kyungsuk Park, Duo Jin, Bin Cai, Bengang Xu, Lauren Connolly, Oswald Steward, Binhai Zheng, Zhigang He
Nature neuroscience 13 (9), 1075-1081 (Sep 2010)
%2C%20.jpg)
Kevin K Park, Kai Liu, Yang Hu, Jennifer L Kanter, Zhigang He
Experimental neurology 223 (1), 45-50 (May 2010)
2009
Yingjie Shen, Alan P Tenney, Sarah A Busch, Kevin P Horn, Fernando X Cuascut, Kai Liu, Zhigang He, Jerry Silver, John G Flanagan
Science 326 (5952), 592-596 (Oct 2009)
2008
Kevin Kyungsuk Park, Kai Liu, Yang Hu, Patrice D Smith, Chen Wang, Bin Cai, Bengang Xu, Lauren Connolly, Ioannis Kramvis, Mustafa Sahin, Zhigang He
Science 322 (5903), 963-966 (Nov 2008)
.jpg)
Benxiu Ji, Lauren C Case, Kai Liu, Zhaohui Shao, Xinhua Lee, Zhongshu Yang, Joy Wang, Tim Tian, Svetlana Shulga-Morskaya, Martin Scott, Zhigang He, Jane K Relton, Sha Mi
Molecular and Cellular Neuroscience 39 (2), 258-267 (Oct 2008)
2007
Tino Riegger, Sabine Conrad, Kai Liu, Hermann J Schluesener, Mahdi Adibzahdeh, Jan M Schwab
European Journal of Neuroscience 25 (6), 1743-1747 (Mar 2007)