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Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction

Neural Regeneration Research 2025年第9期20卷 2464-2479页

作者： Said Hashemolhosseini Lea Gessler Institute of Biochemistry Medical FacultyFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany

Skeletal muscles are essential for locomotion,posture,and metabolic *** understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle *** process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle *** contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular *** muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate *** of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction *** development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as *** regulators coordinate the diffe rentiation of myoblasts into mature muscle *** pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient *** ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal *** interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular *** molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling *** recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular *** fact,research in the last few years now suggests that these two signaling pathways are interconnected and

关键词： canonical Wnt"Wingless-related integration site"pathway beta-catenin(CTNNB1) Hippo pathway myogenesis myotube neuromuscular junction satellite cell skeletal muscle fiber transcriptional co-activator with PDZ-binding motif(TAZ) T-cell-specific transcription factor/lymphoid enhancer-binding factor(TCF/LEF) TEA domain family member(TEAD) transducin-like enhancer of split(TLE) yes-associated protein 1(YAP1)

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Human neuromuscular junction three-dimensional organoid models and the insight in motor disorders

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Journal of Molecular Cell Biology 2021年第11期13卷 767-773页

作者： Kejing Zhang Lei Bai Wentao Xu Chengyong Shen Department of Neurobiology The First Affiliated HospitalInstitute of Translational MedicineSchool of MedicineZhejiang UniversityHangzhou 310020China

The neuromuscular junction(NMJ),a peripheral synaptic connection between motoneurons and skeletal muscle fibers,controls *** of NMJs has been implicated in various motor *** of their large size and easy accessibility,NMJs have been extensively investigated in the neuroscience field and have greatly contributed to our understanding of the fundamental principles of synapses in the central nervous *** have tried multiple ways to develop models to recreate *** progress in the research and development of tissue-like organoids has made it possible to produce human NMJ three-dimensional(3D)models in vitro,providing an additional powerful strategy to study ***,we introduce the most recent advances of human embryonic stem cell-or induced pluripotent stem cell-derived organoids to model 3D NMJs.

关键词： neuromuscular junction organoid motor disorder

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TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

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Translational Neurodegeneration 2022年第1期11卷 46-69页

作者： Sarah Lépine Maria José Castellanos-Montiel Thomas Martin Durcan The Neuro’s Early Drug Discovery Unit(EDDU) Department of Neurology and NeurosurgeryMontreal Neurological Institute-HospitalMcGill University3801 University StreetMontrealQC H3A 2B4Canada Faculty of Medicine and Health Sciences McGill University3605 De La MontagneMontrealQC H3G 2M1Canada

Amyotrophic lateral sclerosis(ALS)is a disease characterized by upper and lower motor neuron(MN)loss with a signature feature of cytoplasmic aggregates containing TDP-43,which are detected in nearly all *** in the gene that encodes TDP-43(TARBDP)are known to result in both familial and sporadic *** ALS,disruption of neuro-muscular junctions(NMJs)constitutes a critical event in disease pathogenesis,leading to denervation atrophy,motor impairments and *** defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro,linking TDP-43 dysregulation to the loss of NMJ integrity in *** the lens of the dying-back and dying-forward hypotheses of ALS,this review discusses the roles of TDP-43 related to synaptic function,with a focus on the potential molecular mechanisms occurring within MNs,skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.

关键词： Amyotrophic lateral sclerosis Denervation neuromuscular junction TDP-43 Dying-back Dying-forward

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Atrial Septal Defect, neuromuscular junction and Skeletal Abnormalities in Spinal Muscular Atrophy Type Ⅲ

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Chinese Medical Journal 2017年第19期130卷 2382-2383页

作者： Xing-Hua Luan Jun Liu Department of Neurology and Institute of Neurology Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine Shanghai 200025 China

Spinal muscular atrophy （SMA） is a genetic disorder which is clinically characterized by progressive muscle weakness and atrophy and is associated with the degeneration of spinal and lowers bulbar motor neurons. SMAis the most common genetic cause of infant mortality, and seems to be present in general populations. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness. Approximately 81.2–95.0% of cases of SMA resulted from homozygous deletion of survival of motor neuron 1 （SMN1） and 5.0% were compound heterozygous patients.[1] SMA might manifest not only the dysfunction of pure motor neurons but also abnormalities in neuromuscular junction （NMJ）, osteoporotic bone formation, cardiac abnormalities, and vascular defects.[2] These phenomena have been described in severe SMA （Type I, II） patients and in mouse models while data from SMA Type III individuals are not available. Patients with SMA Type III demonstrate progressive proximal weakness affecting the legs more severely than the arms, and might ultimately end up in the wheelchair. Herein, we report one patient with SMA Type III manifesting an atrial septal defect （ASD）, NMJ defect, short stature, and thick toes.

关键词： Atrial Septal Defect Multi-organ Diseases neuromuscular junction Skeletal Abnormalities Spinal Muscular Atrophy Type Ⅲ

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EFFECTS OF MANGANESE ON neuromuscular junction TRANSMISSION

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Journal of Pharmaceutical Analysis 1994年第1期8卷 1-4,10页

作者：曹永孝车锡平王长江李卫红 Department of Pharmacology Faculty of Pharmacy Xi'an Medical University Xi'an 710061 China

The effects of manganese on neuromuscular junction transmission were studied in the isolated rat phrenic nerve diaphragm preparation, chick biventer cervicis nerve-muscle preparation and toad rectus abdominis muscle preparation. It wa found that manganese could adversely andconcentration-dependently inhibit muscular contraction response developed by indirect stimulation or direct stimulation. The IC50 of indirect and direct stimulation were 0.28 mmol/L and 10 mmol/Lrespectively. The time required to inhibit 50% of the contraction by indirect stimulation was 4.3±1. 0 min. The inhibitory action could be antagonized partially by high Ca2+. Manganese could reduce the seusitivity of the chick biventer cervicis muscle to acetylcholine, and shift the dose-respond curves foracetylcholine to the right in a nonparallel manner with a pD2' value of 2. 62. The result suggested that manganese acted on pre- and post-synaptic sites.

关键词： manganese neuromuscular junction phrenic nerve diaphragm chick biventer Cervicis

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Active zone stability:insights from fly neuromuscular junction

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Neural Regeneration Research 2015年第5期10卷 677-678页

作者： Xiaolin Tian Chunlai Wu Neuroscience Center of Excellence Department of Cell Biology and AnatomySchool of MedicineLouisiana State University Health Sciences Center

The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study- ing a model synapse, the Drosophila neuromuscular iunction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos- phorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research.

关键词： active zone stability Drosophila neuromuscular junction dephosphorylation Liprin-α Syd-1 PP2A GSK-3β

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Rapsyn interaction with calpain stabilizes AChR clusters at the neuromuscular junction

Rapsyn interaction with calpain stabilizes AChR clusters at ...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Fei CHEN~*,Lei QIAN~*,Zhen-Ge LUO Institute of Neuroscience and Key Laboratory of Neurobiology,Shanghai Institute for Biological Sciences,Chinese Academy of Sciences,320 Yue Yang Road,Shanghai 200031,China.

＜正＞Agrin induces whereas acetylcholine（ACh） disperses ACh receptor（AChR） clusters during neuromuscular *** counteractive interaction leads to eventual dispersal of non-synaptic AChR rich-sites and formation of receptor clusters at the postjunctional ***,the underlying mechanisms are not well understood. Here we show that calpain,a calcium-dependent protease,is activated by the cholinergic agonist carbachol（CCh） and is required for CCh-induced dispersion of AChR ***,the AChR-associated protein rapsyn interacted with calpain,in an agrin dependent manner,and this interaction inhibited the protease activity of *** the endogenous rapsyn/calpain interaction enhanced CCh-induced dispersion of AChR ***,the loss of AChR clusters in agrin mutant mice was partially rescued by the inhibition of calpain via over-expressing calpastatin,an endogenous calpain inhibitor,or injecting calpeptin,a cell-permeable calpain *** results demonstrate that calpain participates in ACh-induced dispersion of AChR clusters,and rapsyn stabilizes AChR clusters by suppressing calpain activity.

关键词： rapsyn calpain Cdk5 agrin acetylcholine receptor clustering neuromuscular junction

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The role of Gab in the development of neuromuscular junction

The role of Gab in the development of neuromuscular junction

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Jing ZHANG~1,Yue-Hai KE~2,Xiao-Ming LI~(1,*) 1 Department of Neurobiology,Key Laboratory of Medical Neurobiology of Ministry of Health,Zhejiang Province Key Laboratory of Neurobiology,Zhejiang University School of Medicine,Hangzhou 310058,China 2 Department of pathology,Zhejiang University School of Medicine,Hangzhou 310058,China

＜正＞Objective Grb2-associated binder（Gab）docking proteins have crucialroles in neural development. However,the roles of Gab proteins in the development of synapses remain ***,we investigate the role of Gab in the development of synapses using the neuromuscular junction as a model of *** We generated muscle-specific Gab1 mutant but Gab2 null mice by using a loxP/Cre strategy since Gab1 null mutation cause embryonic *** Gabl（floxed/floxed）Gab2 null mice were crossed with mice expressing the Cre gene under the control of the human skeletal alpha-actin（HSA）*** interaction between Gab 1/2 and postsynaptic proteins were identified by co-immunoprecipition assay and Western Blot *** the morphology analysis of the conditional knockout mutation mice was investigated by Immuno-histochemistry and Immuno-fluorescence. Results The conditional knockout（CKO）mice were viable and *** AChR clusters colocalized with markers of presynaptic and postsynaptic ***,in comparison with age-matched littermates,the CKO micehave shown the decrease in the AChR cluster area and diameter at postnatal day *** Gab proteins may contribute to the early development of post-synapses of neuromuscular junction.

关键词： Gab neuromuscular junction AChR synaptic development

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Signaling mechanisms of LRP4 at the neuromuscular junction

Signaling mechanisms of LRP4 at the neuromuscular junction

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中国神经科学学会第十届全国学术会议

作者： Hai-Tao Wu Yi-Sheng Lu Cheng-Yong Shen Lin Gan Ming Fan Wen C Xiong Lin Mei Instttute of Molecular Medicine and Genetics and Department of Neurology Georgia Regents University

neuromuscular junction(NMJ) formation requires precise interaction between motoneurons and muscle *** antegrade signaling,motoneurons direct postsynaptic differentiation by agrin and *** is understood about retrograde mechanisms by which muscle fibers regulate presynaptic ***4 is a single-transmembrane protein that is known to serve as a receptor of motoneuron-derived agrin to stimulate MuSK in muscle fibers for postsynaptic ***,mutant mice(HSA-LRP4’) where LRP4 was specifically knocked out in muscle fibers showed presynaptic as well as postsynaptic *** particular,nerve terminals extended into areas without AChR clusters and the numbers of vesicles and active zones were ***4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of co-cultured neurons,suggesting a synaptogenic *** results suggest a critical role of muscle LRP4 in presynaptic differentiation,identifying a potentially novel retrograde *** addition,our results suggest that muscle LRP4 is involved in deciding where to form AChR clusters in muscle *** of muscle and motoneuron LRP4 double mutants and mechamstic studies suggest that LRP4 in motoneurons may serve as a receptor for agrin in trans for forming immature AChR *** observations uncovered previously unexpected functions of LRP4 in NMJ formation.

关键词： neuromuscular junction agrin LRP4 retrograde AChR

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Ethylene thiourea exposure induces neurobehavioral toxicity in zebrafish by disrupting axon growth and neuromuscular junctions

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Journal of Environmental Sciences 2024年第3期137卷 108-119页

作者： Jingming Wang Zhiquan Yu Yongfeng Wang Yuanyao Chen Lin Xiao Yanjun Zong Qiyuan Feng Lianqi Peng Huiping Zhang Chunyan Liu Institute of Reproductive Health Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Ethylene thiourea(ETU)converted from ethylene bisdithiocarbamate(EBDC)fungicides has aroused great concern because of its prevalence and harmful *** ETU-induced neurotoxicity has been reported,the potential mechanisms remain *** study provided insights into its neurotoxic effects at environmentally relevant concentrations in *** findings showed that embryonic exposure to ETU decreased the hatch rate and delayed somite ***,ETU treatment significantly reduced the dark velocity in the locomotion *** upregulated tendency of the mitogen-activated protein kinases(MAPK)pathway(mknk1,atf4,mapkapk3)screened by transcriptome analysis implied motor neuron degeneration,which was validated by subsequent morphological observation,as axon length and branches were truncated in the 62.5μg/L ETU ***,although the rescue experiment with a p38 MAPK inhibitor(SB203580)successfully ameliorated axon degeneration,it failed to reverse the locomotion *** exploration of transcriptome data revealed the varied expression of presynaptic scaffold protein-related genes(pcloa,pclob,bsna),whose downregulation might impair the neuromuscular junction(NMJ).Therefore,we reasonably suspected that ETU-induced neurobehavioral deficits might result from the combined effects of the MAPK pathway and presynaptic *** this,we highlighted the necessity to take precautions and early interventions for susceptible ETU-exposed populations.

关键词： Ethylene thiourea(ETU) Behavior neuromuscular junction MAPK signaling pathway Piccolo and bassoon Danio rerio

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