Acute mitochondrial damage and the energy crisis following axonal injury highlight mitochondrial transport as an important target for axonal regeneration.Syntaphilin(Snph),known for its potent mitochondrial anchoring ...Acute mitochondrial damage and the energy crisis following axonal injury highlight mitochondrial transport as an important target for axonal regeneration.Syntaphilin(Snph),known for its potent mitochondrial anchoring action,has emerged as a significant inhibitor of both mitochondrial transport and axonal regeneration.Therefore,investigating the molecular mechanisms that influence the expression levels of the snph gene can provide a viable strategy to regulate mitochondrial trafficking and enhance axonal regeneration.Here,we reveal the inhibitory effect of microRNA-146b(miR-146b)on the expression of the homologous zebrafish gene syntaphilin b(snphb).Through CRISPR/Cas9 and single-cell electroporation,we elucidated the positive regulatory effect of the miR-146b-snphb axis on Mauthner cell(M-cell)axon regeneration at the global and single-cell levels.Through escape response tests,we show that miR-146b-snphb signaling positively regulates functional recovery after M-cell axon injury.In addition,continuous dynamic imaging in vivo showed that reprogramming miR-146b significantly promotes axonal mitochondrial trafficking in the pre-injury and early stages of regeneration.Our study reveals an intrinsic axonal regeneration regulatory axis that promotes axonal regeneration by reprogramming mitochondrial transport and anchoring.This regulation involves noncoding RNA,and mitochondria-associated genes may provide a potential opportunity for the repair of central nervous system injury.展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles an...Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo;however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase(PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway.展开更多
Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to p...Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.展开更多
Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system repair.However,this stress response drives neuronal apoptosis in n...Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system repair.However,this stress response drives neuronal apoptosis in non-regenerative environments.This duality presents a quandary for the development of therapeutic interventions:manipulating stress signaling to enhance recovery of damaged neurons risks accelerating neurodegeneration or restricting regenerative potential.This dichotomy is well illustrated by the fates of retinal ganglion cells(RGCs)following optic nerve crush.In this central nervous system injury model,disruption of a stress-activated MAP kinase(MAPK)cascade blocks the extensive apoptosis of RGCs that occurs in wild-type mice(Watkins et al.,2013;Welsbie et al.,2017).展开更多
Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target no...Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.展开更多
During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their el...During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.展开更多
Objective:Treating peripheral nerve injury(PNI)presents a clinical challenge due to limited axon regeneration.Strychni Semen,a traditional Chinese medicine,is clinically used for numbness and hemiplegia.However,its ro...Objective:Treating peripheral nerve injury(PNI)presents a clinical challenge due to limited axon regeneration.Strychni Semen,a traditional Chinese medicine,is clinically used for numbness and hemiplegia.However,its role in promoting functional recovery after PNI and the related mechanisms have not yet been systematically studied.Methods:A mouse model of sciatic nerve crush(SNC)injury was established and the mice received drug treatment via intragastric gavage,followed by behavioral assessments(adhesive removal test,hot-plate test and Von Frey test).Transcriptomic analyses were performed to examine gene expression in the dorsal root ganglia(DRGs)from the third to the sixth lumbar vertebrae,so as to identify the significantly differentially expressed genes.Immunofluorescence staining was used to assess the expression levels of superior cervical ganglia neural-specific 10 protein(SCG10).The ultra-trace protein detection technique was used to evaluate changes in gene expression levels.Results:Strychni Semen and its active compounds(brucine and strychnine)improved functional recovery in mice following SNC injury.Transcriptomic data indicated that Strychni Semen and its active compounds initiated transcriptional reprogramming that impacted cellular morphology and extracellular matrix remodeling in DRGs after SNC,suggesting potential roles in promoting axon regeneration.Imaging data further confirmed that Strychni Semen and its active compounds facilitated axon regrowth in SNC-injured mice.By integrating protein–protein interaction predictions,ultra-trace protein detection,and molecular docking analysis,we identified myeloperoxidase as a potentially critical factor in the axon regenerative effects conferred by Strychni Semen and its active compounds.Conclusion:Strychni Semen and its active compounds enhance sensory function by promoting axonal regeneration after PNI.These findings establish a foundation for the future applications of Strychni Semen and highlight novel therapeutic strategies and drug targets for axon regeneration.展开更多
Erratum to:J Huazhong Univ Sci Technol[Med Sci]36(4):548–553,2016 https://doi.org/10.1007/s11596-016-1623-6 In the originally published article(https://doi.org/10.1007/s11596-016-1623-6),the immunofluorescence images...Erratum to:J Huazhong Univ Sci Technol[Med Sci]36(4):548–553,2016 https://doi.org/10.1007/s11596-016-1623-6 In the originally published article(https://doi.org/10.1007/s11596-016-1623-6),the immunofluorescence images in shRNA group in Fig.3 were accidentally used rather than the final,formal experiments.To retain consistency,the entire Fig.3 is replaced here with original images of the experiments.The authors declare that this correction will not affect the conclusion of the study.展开更多
MicroRNAs(miRNAs)play a significant role in axon regeneration following spinal cord injury.However,the functions of numerous miRNAs in axon regeneration within the central nervous system(CNS)remain largely unexplored....MicroRNAs(miRNAs)play a significant role in axon regeneration following spinal cord injury.However,the functions of numerous miRNAs in axon regeneration within the central nervous system(CNS)remain largely unexplored.Here,we elucidate the positive role of microRNA-2184(miR-2184)in axon regeneration within zebrafish Mauthner cells(M-cells).The upregulation of miR-2184 in a single M-cell can facilitate axon regeneration,while the specific sponge-induced silencing of miR-2184 leads to impeded regeneration.We show that syt3,a downstream target of miR-2184,negatively regulates axon regeneration,and the regeneration suppression modulated by syt3 depends on its binding to Ca^(2+).Furthermore,pharmacological stimulation of the cAMP/PKA pathway suggests that changes in the readily releasable pool may affect axon regeneration.Our data indicate that miR-2184 promotes axon regeneration of M-cells within the CNS by modulating the downstream target syt3,providing valuable insights into potential therapeutic strategies.展开更多
Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and foun...Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury.Platelet factor is an important molecule in cell apoptosis,diffe rentiation,survival,and proliferation.Further,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury.Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells.We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon growth.Furthermore,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic nerve.These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth.Thus,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.展开更多
Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside a...Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.展开更多
The assembly of neurons into complex circuits relies upon appropriate axonal navigation to distant targets.Although considerable progress has been made toward understanding the regulation of the guidance and branching...The assembly of neurons into complex circuits relies upon appropriate axonal navigation to distant targets.Although considerable progress has been made toward understanding the regulation of the guidance and branching of axon extension,the molecular and cellular mechanisms underlying the coordination of the motility of the axon tip,axon growth,and branching remain largely unknown(Sudhof,2017).The Drosophila mushroom body(MB),the major site for associative learning and memory,is a powerful model system to investigate complex axon behaviors.The MB is a bilaterally symmetric central brain structure,mainly composed of Kenyon cells,MB output neurons,and dopaminergic neurons(Li et al.,2020).Among the seven neuronal subtypes of~2000 Kenyon cells,Y,a/β,and a/β'subtypes extend axons in a fascicle and bifurcate to produce two sister branches,one projecting into the dorsal lobe and the other into the medial lobe.展开更多
Amyotrophic Lateral Sclerosis(ALS)is a complex neurodegenerative disorder characterized by progressive axonopathy,jointly leading to the dying back of the motor neuron,disrupting both nerve signaling and motor control...Amyotrophic Lateral Sclerosis(ALS)is a complex neurodegenerative disorder characterized by progressive axonopathy,jointly leading to the dying back of the motor neuron,disrupting both nerve signaling and motor control.In this review,we highlight the roles of axonopathy in ALS progression,driven by the interplay of multiple factors including defective trafficking machinery,protein aggregation,and mitochondrial dysfunction.Dysfunctional intracellular transport,caused by disruptions in microtubules,molecular motors,and adaptors,has been identified as a key contributor to disease progression.Aberrant protein aggregation involving TDP-43,FUS,SOD1,and dipeptide repeat proteins further amplifies neuronal toxicity.Mitochondrial defects lead to ATP depletion,oxidative stress,and Ca2+imbalance,which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy.Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential.Collaborative research efforts aim to unravel ALS complexities,opening avenues for holistic interventions that target diverse pathological mechanisms.展开更多
Axon initial segment(AIS)is the most excitable subcellular domain of a neuron for action potential initiation.AISs of cortical projection neurons(PNs)receive GABAergic synaptic inputs primarily from chandelier cells(C...Axon initial segment(AIS)is the most excitable subcellular domain of a neuron for action potential initiation.AISs of cortical projection neurons(PNs)receive GABAergic synaptic inputs primarily from chandelier cells(ChCs),which are believed to regulate action potential generation and modulate neuronal excitability.As individual ChCs often innervate hundreds of PNs,they may alter the activity of PN ensembles and even impact the entire neural network.During postnatal development or in response to changes in network activity,the AISs and axo-axonic synapses undergo dynamic structural and functional changes that underlie the wiring,refinement,and adaptation of cortical microcircuits.Here we briefly introduce the history of ChCs and review recent research advances employing modern genetic and molecular tools.Special attention will be attributed to the plasticity of the AIS and the ChC-PN connections,which play a pivotal role in shaping the dynamic network under both physiological and pathological conditions.展开更多
This paper derives rigorous statements concerning the propagation velocity of action potentials in axons. The authors use the Green’s function approach to approximate the action potential and find a relation between ...This paper derives rigorous statements concerning the propagation velocity of action potentials in axons. The authors use the Green’s function approach to approximate the action potential and find a relation between conduction velocity and the impulse profile. Computer simulations are used to bolster the analysis.展开更多
In this paper, we present a simulation program that allows for the concurrent propagation of action potentials in axons coupled via currents, as well as, for the first time, the computation of the resultant nodal elec...In this paper, we present a simulation program that allows for the concurrent propagation of action potentials in axons coupled via currents, as well as, for the first time, the computation of the resultant nodal electric field generated as the action potentials traverse the tract of axons. With these fields in hand, we inject currents into nodes of axons that depend on these fields and study the coupling between axons in the presence of the fields and currents present jointly in varying strengths. We find close-to-synchronized propagation in three dimensions. Further, we derive for the first time a mathematical equation for tortuous tracts (as opposed to linear) with such field-mediated coupling. The geometrical formulation enables us to consider spacetime perturbative effects, which have also not been considered in the literature so far. We investigate the case when gravitational radiation is present, in order to determine its impact on tract information processing. We find that action potential relative-timing in a tract is affected by the strength and frequency of gravitational waves and the waning of this influence with weakening strength. This latter study blurs the division between what lies inside and outside man. As an additional novelty, we investigate the influence of geometry on the information transmission capacity of the ephaptically-coupled tract, when viewed as a discrete memoryless channel, and find a rising trend in capacity with increasing axonal inclinations, which may occur in traumatic CNS injury.展开更多
Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor co...Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.展开更多
Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic a...Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2（CRMP2） might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.展开更多
Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconne...Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconnection from their targets,which in turn leads to functional impairment.During the course of many of neurologic diseases,axons can regenerate or sprout in an attempt to reconnect with the target and restore synapse function.In amyotrophic lateral sclerosis(ALS),distal motor axons retract from neuromuscular junctions early in the disease-course before significant motor neuron death.There is evidence of compensatory motor axon sprouting and reinnervation of neuromuscular junctions in ALS that is usually quickly overtaken by the disease course.Potential drugs that enhance compensatory sprouting and encourage reinnervation may slow symptom progression and retain muscle function for a longer period of time in ALS and in other diseases that exhibit dying-back axonopathy.There remain many outstanding questions as to the impact of distinct disease-causing mutations on axonal outgrowth and regeneration,especially in regards to motor neurons derived from patient induced pluripotent stem cells.Compartmentalized microfluidic chambers are powerful tools for studying the distal axons of human induced pluripotent stem cells-derived motor neurons,and have recently been used to demonstrate striking regeneration defects in human motor neurons harboring ALS disease-causing mutations.Modeling the human neuromuscular circuit with human induced pluripotent stem cells-derived motor neurons will be critical for developing drugs that enhance axonal regeneration,sprouting,and reinnervation of neuromuscular junctions.In this review we will discuss compensatory axonal sprouting as a potential therapeutic target for ALS,and the use of compartmentalized microfluidic devices to find drugs that enhance regeneration and axonal sprouting of motor axons.展开更多
基金supported by the core facility Center for Life Sciences,University of Science and Technology of China,Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYZD20220002)the National Natural Science Foundation of China(82071357)the Ministry of Science and Technology of China(2019YFA0405600).
文摘Acute mitochondrial damage and the energy crisis following axonal injury highlight mitochondrial transport as an important target for axonal regeneration.Syntaphilin(Snph),known for its potent mitochondrial anchoring action,has emerged as a significant inhibitor of both mitochondrial transport and axonal regeneration.Therefore,investigating the molecular mechanisms that influence the expression levels of the snph gene can provide a viable strategy to regulate mitochondrial trafficking and enhance axonal regeneration.Here,we reveal the inhibitory effect of microRNA-146b(miR-146b)on the expression of the homologous zebrafish gene syntaphilin b(snphb).Through CRISPR/Cas9 and single-cell electroporation,we elucidated the positive regulatory effect of the miR-146b-snphb axis on Mauthner cell(M-cell)axon regeneration at the global and single-cell levels.Through escape response tests,we show that miR-146b-snphb signaling positively regulates functional recovery after M-cell axon injury.In addition,continuous dynamic imaging in vivo showed that reprogramming miR-146b significantly promotes axonal mitochondrial trafficking in the pre-injury and early stages of regeneration.Our study reveals an intrinsic axonal regeneration regulatory axis that promotes axonal regeneration by reprogramming mitochondrial transport and anchoring.This regulation involves noncoding RNA,and mitochondria-associated genes may provide a potential opportunity for the repair of central nervous system injury.
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
基金supported by the Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM,No.QYZD20220002the National Natural Science Foundation of China,No.82071357a grant from the Ministry of Science and Technology of China,No.2019YFA0405600 (all to BH)。
文摘Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo;however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase(PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway.
基金supported by the Natio`nal Natural Science Foundation of China,No. 81801241a grant from Sichuan Science and Technology Program,No. 2023NSFSC1578Scientific Research Projects of Southwest Medical University,No. 2022ZD002 (all to JX)。
文摘Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.
基金supported by grants from Mission Connect, a project of the TIRR Foundation, the Glaucoma Research FoundationNIH grants R01NS112691 and R01NS076708 (to TAW)
文摘Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system repair.However,this stress response drives neuronal apoptosis in non-regenerative environments.This duality presents a quandary for the development of therapeutic interventions:manipulating stress signaling to enhance recovery of damaged neurons risks accelerating neurodegeneration or restricting regenerative potential.This dichotomy is well illustrated by the fates of retinal ganglion cells(RGCs)following optic nerve crush.In this central nervous system injury model,disruption of a stress-activated MAP kinase(MAPK)cascade blocks the extensive apoptosis of RGCs that occurs in wild-type mice(Watkins et al.,2013;Welsbie et al.,2017).
基金supported by the National Natural Science Foundation of China,Nos. 81760247, 82171450the Scientific Research Foundation for Doctors of the Affiliated Hospital of Zunyi Medical University,No.(2016)14 (all to HH)。
文摘Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.
基金supported by Catalan Government,Nos.2014SGR344(to JT),2017SGR704(to JT),2021SGR01214(to MAL)MCIN/AEI/10.13039/501100011033/by“ERDF A way of making Europe,”Nos.SAF2015-67143(to JT),PID2019-106332GB-I00(to JT and MAL)and PID2022-141252NB-I00(to MAL).
文摘During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
基金financially supported by the National Natural Science Foundation of China(No.82474420,No.82273903)。
文摘Objective:Treating peripheral nerve injury(PNI)presents a clinical challenge due to limited axon regeneration.Strychni Semen,a traditional Chinese medicine,is clinically used for numbness and hemiplegia.However,its role in promoting functional recovery after PNI and the related mechanisms have not yet been systematically studied.Methods:A mouse model of sciatic nerve crush(SNC)injury was established and the mice received drug treatment via intragastric gavage,followed by behavioral assessments(adhesive removal test,hot-plate test and Von Frey test).Transcriptomic analyses were performed to examine gene expression in the dorsal root ganglia(DRGs)from the third to the sixth lumbar vertebrae,so as to identify the significantly differentially expressed genes.Immunofluorescence staining was used to assess the expression levels of superior cervical ganglia neural-specific 10 protein(SCG10).The ultra-trace protein detection technique was used to evaluate changes in gene expression levels.Results:Strychni Semen and its active compounds(brucine and strychnine)improved functional recovery in mice following SNC injury.Transcriptomic data indicated that Strychni Semen and its active compounds initiated transcriptional reprogramming that impacted cellular morphology and extracellular matrix remodeling in DRGs after SNC,suggesting potential roles in promoting axon regeneration.Imaging data further confirmed that Strychni Semen and its active compounds facilitated axon regrowth in SNC-injured mice.By integrating protein–protein interaction predictions,ultra-trace protein detection,and molecular docking analysis,we identified myeloperoxidase as a potentially critical factor in the axon regenerative effects conferred by Strychni Semen and its active compounds.Conclusion:Strychni Semen and its active compounds enhance sensory function by promoting axonal regeneration after PNI.These findings establish a foundation for the future applications of Strychni Semen and highlight novel therapeutic strategies and drug targets for axon regeneration.
文摘Erratum to:J Huazhong Univ Sci Technol[Med Sci]36(4):548–553,2016 https://doi.org/10.1007/s11596-016-1623-6 In the originally published article(https://doi.org/10.1007/s11596-016-1623-6),the immunofluorescence images in shRNA group in Fig.3 were accidentally used rather than the final,formal experiments.To retain consistency,the entire Fig.3 is replaced here with original images of the experiments.The authors declare that this correction will not affect the conclusion of the study.
基金supported by the Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYZD20220002)the National Natural Science Foundation of China(82071357)the Ministry of Science and Technology of China(2019YFA0405600 to B.H.).
文摘MicroRNAs(miRNAs)play a significant role in axon regeneration following spinal cord injury.However,the functions of numerous miRNAs in axon regeneration within the central nervous system(CNS)remain largely unexplored.Here,we elucidate the positive role of microRNA-2184(miR-2184)in axon regeneration within zebrafish Mauthner cells(M-cells).The upregulation of miR-2184 in a single M-cell can facilitate axon regeneration,while the specific sponge-induced silencing of miR-2184 leads to impeded regeneration.We show that syt3,a downstream target of miR-2184,negatively regulates axon regeneration,and the regeneration suppression modulated by syt3 depends on its binding to Ca^(2+).Furthermore,pharmacological stimulation of the cAMP/PKA pathway suggests that changes in the readily releasable pool may affect axon regeneration.Our data indicate that miR-2184 promotes axon regeneration of M-cells within the CNS by modulating the downstream target syt3,providing valuable insights into potential therapeutic strategies.
基金supported by the National Natural Science Foundation of China,Nos.31730031,32130060the National Natural Science Foundation of China,No.31971276(to JH)+1 种基金the Natural Science Foundation of Jiangsu Province,No.BK20202013(to XG)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.19KJA320005(to JH)。
文摘Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury.Platelet factor is an important molecule in cell apoptosis,diffe rentiation,survival,and proliferation.Further,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury.Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells.We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon growth.Furthermore,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic nerve.These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth.Thus,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.
基金supported by Fondo para la Investigación Cientifica y Tecnológica(FONCy T),Argentina,grant#PICT 2015-2473(to PHHL)supported by grants from National Institute of Health/National Institute of Neurological Disorders and Stroke(NIH/NINDS,USA)(NS121621)+2 种基金Department of Defense,USA(Do D-CL1)(PR200530)partially financed with a fellowship for Research in Medicine from Fundación Florencio Fiorinisupported with a PhD fellowship from CONICET。
文摘Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.
基金supported by research grants from the National Natural Science Foundation of China(31871461 and 31671510 to H.H.).
文摘The assembly of neurons into complex circuits relies upon appropriate axonal navigation to distant targets.Although considerable progress has been made toward understanding the regulation of the guidance and branching of axon extension,the molecular and cellular mechanisms underlying the coordination of the motility of the axon tip,axon growth,and branching remain largely unknown(Sudhof,2017).The Drosophila mushroom body(MB),the major site for associative learning and memory,is a powerful model system to investigate complex axon behaviors.The MB is a bilaterally symmetric central brain structure,mainly composed of Kenyon cells,MB output neurons,and dopaminergic neurons(Li et al.,2020).Among the seven neuronal subtypes of~2000 Kenyon cells,Y,a/β,and a/β'subtypes extend axons in a fascicle and bifurcate to produce two sister branches,one projecting into the dorsal lobe and the other into the medial lobe.
基金supported by the National Natural Science Foundation of China(32271001 and 31871036).
文摘Amyotrophic Lateral Sclerosis(ALS)is a complex neurodegenerative disorder characterized by progressive axonopathy,jointly leading to the dying back of the motor neuron,disrupting both nerve signaling and motor control.In this review,we highlight the roles of axonopathy in ALS progression,driven by the interplay of multiple factors including defective trafficking machinery,protein aggregation,and mitochondrial dysfunction.Dysfunctional intracellular transport,caused by disruptions in microtubules,molecular motors,and adaptors,has been identified as a key contributor to disease progression.Aberrant protein aggregation involving TDP-43,FUS,SOD1,and dipeptide repeat proteins further amplifies neuronal toxicity.Mitochondrial defects lead to ATP depletion,oxidative stress,and Ca2+imbalance,which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy.Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential.Collaborative research efforts aim to unravel ALS complexities,opening avenues for holistic interventions that target diverse pathological mechanisms.
基金supported by the National Science and Technology Innovation 2030 Major Projects of China(STI2030-Major Projects-2022ZD0206500)the National Natural Science Foundation of China(32371006,32171087,82071450).
文摘Axon initial segment(AIS)is the most excitable subcellular domain of a neuron for action potential initiation.AISs of cortical projection neurons(PNs)receive GABAergic synaptic inputs primarily from chandelier cells(ChCs),which are believed to regulate action potential generation and modulate neuronal excitability.As individual ChCs often innervate hundreds of PNs,they may alter the activity of PN ensembles and even impact the entire neural network.During postnatal development or in response to changes in network activity,the AISs and axo-axonic synapses undergo dynamic structural and functional changes that underlie the wiring,refinement,and adaptation of cortical microcircuits.Here we briefly introduce the history of ChCs and review recent research advances employing modern genetic and molecular tools.Special attention will be attributed to the plasticity of the AIS and the ChC-PN connections,which play a pivotal role in shaping the dynamic network under both physiological and pathological conditions.
文摘This paper derives rigorous statements concerning the propagation velocity of action potentials in axons. The authors use the Green’s function approach to approximate the action potential and find a relation between conduction velocity and the impulse profile. Computer simulations are used to bolster the analysis.
文摘In this paper, we present a simulation program that allows for the concurrent propagation of action potentials in axons coupled via currents, as well as, for the first time, the computation of the resultant nodal electric field generated as the action potentials traverse the tract of axons. With these fields in hand, we inject currents into nodes of axons that depend on these fields and study the coupling between axons in the presence of the fields and currents present jointly in varying strengths. We find close-to-synchronized propagation in three dimensions. Further, we derive for the first time a mathematical equation for tortuous tracts (as opposed to linear) with such field-mediated coupling. The geometrical formulation enables us to consider spacetime perturbative effects, which have also not been considered in the literature so far. We investigate the case when gravitational radiation is present, in order to determine its impact on tract information processing. We find that action potential relative-timing in a tract is affected by the strength and frequency of gravitational waves and the waning of this influence with weakening strength. This latter study blurs the division between what lies inside and outside man. As an additional novelty, we investigate the influence of geometry on the information transmission capacity of the ephaptically-coupled tract, when viewed as a discrete memoryless channel, and find a rising trend in capacity with increasing axonal inclinations, which may occur in traumatic CNS injury.
文摘Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.
文摘Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2（CRMP2） might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.
基金This work was supported by the Muscular Dystrophy Association,No.W81XWH1910229(to MHF)from Department of Defense’s Congressionally Directed Medical Research Program,and Maryland Stem Cell Research Fund,No.2019-MSCRFD-5093(to MHF).
文摘Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconnection from their targets,which in turn leads to functional impairment.During the course of many of neurologic diseases,axons can regenerate or sprout in an attempt to reconnect with the target and restore synapse function.In amyotrophic lateral sclerosis(ALS),distal motor axons retract from neuromuscular junctions early in the disease-course before significant motor neuron death.There is evidence of compensatory motor axon sprouting and reinnervation of neuromuscular junctions in ALS that is usually quickly overtaken by the disease course.Potential drugs that enhance compensatory sprouting and encourage reinnervation may slow symptom progression and retain muscle function for a longer period of time in ALS and in other diseases that exhibit dying-back axonopathy.There remain many outstanding questions as to the impact of distinct disease-causing mutations on axonal outgrowth and regeneration,especially in regards to motor neurons derived from patient induced pluripotent stem cells.Compartmentalized microfluidic chambers are powerful tools for studying the distal axons of human induced pluripotent stem cells-derived motor neurons,and have recently been used to demonstrate striking regeneration defects in human motor neurons harboring ALS disease-causing mutations.Modeling the human neuromuscular circuit with human induced pluripotent stem cells-derived motor neurons will be critical for developing drugs that enhance axonal regeneration,sprouting,and reinnervation of neuromuscular junctions.In this review we will discuss compensatory axonal sprouting as a potential therapeutic target for ALS,and the use of compartmentalized microfluidic devices to find drugs that enhance regeneration and axonal sprouting of motor axons.
