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Cellular and Molecular Life Sciences :... Jun 2021Neuromuscular system is constituted of multi-fibrillar muscles, tendons, motor neurons and associated muscle stem cells. Stereotyped pattern of muscle innervation and... (Review)
Review
Neuromuscular system is constituted of multi-fibrillar muscles, tendons, motor neurons and associated muscle stem cells. Stereotyped pattern of muscle innervation and muscle-specific interactions with tendon cells suggest that neuromuscular system develops in a coordinated way. Remarkably, upon regeneration, coordinated assembly of all neuromuscular components is also critical to rebuild functional muscle. Thus, to ensure muscle function, the neuromuscular system components need to interact both during development and regeneration. Over the last decades, interactions between muscles and tendons, muscles and motor neurons and between muscles and muscle stem cells have been extensively analysed and documented. However, only recent evidence indicates that muscle stem cells interact with motor neurons and that these interactions contribute to building functional muscle both during development and regeneration. From this perspective, we discuss here the relationship between muscle stem cells and motor neurons during Drosophila neuromuscular system development and adverse impact of affected muscle stem cell-motor neuron interactions in regenerating vertebrate muscle.
Topics: Animals; Humans; Motor Neurons; Muscles; Neuromuscular Junction; Regeneration; Stem Cells
PubMed: 33861361
DOI: 10.1007/s00018-021-03838-2 -
Respiratory Physiology & Neurobiology Jul 2019Respiratory motor neuron death arises from multiple neurodegenerative and traumatic neuromuscular disorders. Despite motor neuron death, compensatory mechanisms minimize... (Review)
Review
Respiratory motor neuron death arises from multiple neurodegenerative and traumatic neuromuscular disorders. Despite motor neuron death, compensatory mechanisms minimize its functional impact by harnessing intrinsic mechanisms of compensatory respiratory plasticity. However, the capacity for compensation eventually reaches limits and pathology ensues. Initially, challenges to the system such as increased metabolic demand reveal sub-clinical pathology. With greater motor neuron loss, the eventual result is de-compensation, ventilatory failure, ventilator dependence and then death. In this brief review, we discuss recent advances in our understanding of mechanisms giving rise to compensatory respiratory plasticity in response to respiratory motor neuron death including: 1) increased central respiratory drive, 2) plasticity in synapses on spared phrenic motor neurons, 3) enhanced neuromuscular transmission and 4) shifts in respiratory muscle utilization from more affected to less affected motor pools. Some of these compensatory mechanisms may prolong breathing function, but hasten the demise of surviving motor neurons. Improved understanding of these mechanisms and their impact on survival of spared motor neurons will guide future efforts to develop therapeutic interventions that preserve respiratory function with neuromuscular injury/disease.
Topics: Animals; Cell Death; Humans; Motor Neurons; Neuromuscular Diseases; Neuronal Plasticity; Phrenic Nerve; Recruitment, Neurophysiological; Respiration; Respiratory Center; Respiratory Muscles
PubMed: 30625378
DOI: 10.1016/j.resp.2019.01.001 -
Developmental Dynamics : An Official... Apr 2018Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key... (Review)
Review
Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key components of the sensory system, are located in the dorsal root ganglia and project axons both centrally to the spinal cord and peripherally to muscles and tendons, communicating peripheral information about the body to the CNS. Changes in muscle length detected by muscle spindles, and tension variations in tendons conveyed by Golgi tendon organs, are communicated to the CNS through group Ia /II, and Ib proprioceptive sensory afferents, respectively. Group Ib proprioceptive sensory neurons connect with motor neurons indirectly through spinal interneurons, whereas group Ia/II axons form both direct (monosynaptic) and indirect connections with motor neurons. Although monosynaptic sensory-motor circuits between spindle proprioceptive sensory neurons and motor neurons have been extensively studied since 1950s, the molecular mechanisms underlying their formation and upkeep have only recently begun to be understood. We will discuss our current understanding of the molecular foundation of monosynaptic circuit development and maintenance involving proprioceptive sensory neurons and motor neurons in the mammalian spinal cord. Developmental Dynamics 247:581-587, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Central Nervous System; Humans; Motor Neurons; Proprioception; Sensory Receptor Cells; Spinal Cord
PubMed: 29226492
DOI: 10.1002/dvdy.24611 -
Restorative Neurology and Neuroscience 2013After a cut peripheral nerve is repaired, motor neurons usually regenerate across the lesion site, however they often enter an inappropriate Schwann cell tube and may be...
PURPOSE
After a cut peripheral nerve is repaired, motor neurons usually regenerate across the lesion site, however they often enter an inappropriate Schwann cell tube and may be directed to an inappropriate target organ such as skin, resulting in continued loss of function. In fact, only about 10% of adults who receive a peripheral nerve repair display full functional recovery. The reasons for this are many and complex, however one aspect is whether the motor neuron has undergone a prolonged period of axotomy prior to nerve repair. Previous studies have suggested a deleterious effect of prolonged axotomy.
METHODS
We examined the influence of prolonged axotomy on target selectivity using a cross-reinnervation model of rat obturator motor neurons regrowing into the distal femoral nerve, with its normal bifurcating pathways to muscle and skin.
RESULTS
Surprisingly, we found that a prolonged period of axotomy resulted in an increase in motor neuron regeneration accuracy. In addition, we found that regeneration accuracy could be increased even further by a simple surgical manipulation of the distal terminal nerve pathway to skin.
CONCLUSIONS
These results suggest that under certain conditions prolonged axotomy may not be detrimental to the final accuracy of motor neuron regeneration and highlight that a simple manipulation of terminal nerve pathways may be one approach to increase such regeneration accuracy.
Topics: Analysis of Variance; Animals; Axotomy; Cell Count; Cell Survival; Disease Models, Animal; Female; Femoral Neuropathy; Motor Neurons; Nerve Regeneration; Rats; Rats, Sprague-Dawley; Recovery of Function
PubMed: 23648674
DOI: 10.3233/RNN-120301 -
Philosophical Transactions of the Royal... Sep 2018The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm.... (Review)
Review
The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm. These studies propose that the A- and mid-body B-class excitatory motor neurons at the ventral cord function as non-bursting intrinsic oscillators to underlie body undulation during reversal and forward movements, respectively. Proprioception entrains their intrinsic activities, allows phase-coupling between members of the same class motor neurons, and thereby facilitates directional propagation of undulations. Distinct pools of premotor interneurons project along the ventral nerve cord to innervate all members of the A- and B-class motor neurons, modulating their oscillations, as well as promoting their bi-directional coupling. The two motor sub-circuits, which consist of oscillators and descending inputs with distinct properties, form the structural base of dynamic rhythmicity and flexible partition of the forward and backward motor states. These results contribute to a continuous effort to establish a mechanistic and dynamic model of the sensorimotor system. exhibits rich sensorimotor functions despite a small neuron number. These findings implicate a circuit-level functional compression. By integrating the role of rhythm generation and proprioception into motor neurons, and the role of descending regulation of oscillators into premotor interneurons, this numerically simple nervous system can achieve a circuit infrastructure analogous to that of anatomically complex systems. has manifested itself as a compact model to search for general principles of sensorimotor behaviours.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling at cellular resolution'.
Topics: Animals; Caenorhabditis elegans; Interneurons; Locomotion; Motor Neurons; Periodicity
PubMed: 30201835
DOI: 10.1098/rstb.2017.0370 -
Neurobiology of Disease Dec 2018Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83...
Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83 mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83 mice, as revealed by unbiased transcriptomic analyses. Our findings provide insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.
Topics: Animals; Brain; Female; Humans; Inflammation; Male; Mice; Mice, Transgenic; Motor Neurons; Nerve Degeneration; Spinal Cord; alpha-Synuclein
PubMed: 30195075
DOI: 10.1016/j.nbd.2018.09.005 -
Cell and Tissue Research Oct 2020Glial cell line-derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial... (Review)
Review
Glial cell line-derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system.
Topics: Biological Transport; Glial Cell Line-Derived Neurotrophic Factor; Humans; Motor Neurons; Signal Transduction
PubMed: 32897420
DOI: 10.1007/s00441-020-03287-6 -
Brain : a Journal of Neurology Apr 2020Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical... (Review)
Review
Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical outcomes stem from the specific neuronal component involved in each condition. While mutations in a large number of molecules associated with lipid metabolism are known to be implicated in MNDs, there remains a lack of clarity regarding the key functional pathways involved, and their inter-relationships. This review highlights evidence that defines defects within two specific lipid (cholesterol/oxysterol and phosphatidylethanolamine) biosynthetic cascades as being centrally involved in MND, particularly hereditary spastic paraplegia. We also identify how other MND-associated molecules may impact these cascades, in particular through impaired organellar interfacing, to propose 'subcellular lipidome imbalance' as a likely common pathomolecular theme in MND. Further exploration of this mechanism has the potential to identify new therapeutic targets and management strategies for modulation of disease progression in hereditary spastic paraplegias and other MNDs.
Topics: Animals; Humans; Lipid Metabolism; Motor Neurons; Neurodegenerative Diseases
PubMed: 31848577
DOI: 10.1093/brain/awz382 -
Current Opinion in Neurobiology Feb 2017Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much... (Review)
Review
Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much attention has been given to the role of networks of spinal interneurons on setting the rhythm and pattern of output from locomotor circuits, recent studies suggest that motor neurons themselves can exert an instructive role in shaping the wiring and functional properties of locomotor networks. Alteration in the distribution of motor neuron subtypes also appears to have contributed to evolutionary transitions in the locomotor strategies used by land vertebrates. This review describes emerging evidence that motor neuron-derived cues can have a profound influence on the organization, wiring, and evolutionary diversification of locomotor circuits.
Topics: Animals; Interneurons; Locomotion; Motor Neurons; Vertebrates
PubMed: 27907815
DOI: 10.1016/j.conb.2016.11.005 -
Cell Adhesion & Migration 2012Spinal motor neurons are critical to the ability of animals to move and thus essential to survival. Motor neurons that project axons to distinct limb-muscle targets are... (Review)
Review
Spinal motor neurons are critical to the ability of animals to move and thus essential to survival. Motor neurons that project axons to distinct limb-muscle targets are topographically organized such that central nervous system position reflects the location of the muscle in the limb. The central positioning of limb-projecting motor neurons arises during development through motor neuron migration followed by a period of coalescence into discrete groupings of motor neurons which project axons to an individual muscle. These so-called motor pools are a common feature of motor organization in higher vertebrates. Recent work has highlighted the critical role for armadillo family member catenin-dependent functions of the cadherin family of cell adhesion molecules in directing the organization of motor neurons. Cadherin function appears to be important for both the motor neuron migration and coalescence phases of the emergence of motor neuron topography. Here, I review this recent work in the context of our understanding of the general development of spinal motor neurons.
Topics: Animals; Cadherins; Catenins; Cell Adhesion; Cell Division; Cell Movement; Chick Embryo; Motor Neurons; Protein Binding; Protein Interaction Mapping; Signal Transduction; Spinal Cord
PubMed: 22902765
DOI: 10.4161/cam.21044