scholarly journals Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

2021 ◽  
Author(s):  
Mathieu Bartoletti ◽  
Tracy Knight ◽  
Aaron Held ◽  
Laura M. Rand ◽  
Kristi A. Wharton
Keyword(s):  
Nervous System ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Development ◽  
Growth Function ◽  
Bmp Signaling ◽  
Autocrine Signaling ◽  
Loss Of Function ◽  
Synaptic Growth

ABSTRACTThe nervous system is a complex network of cells whose interactions provide circuitry necessary for an organism to perceive and move through its environment. Revealing the molecular basis of how neurons and non-neuronal glia communicate is essential for understanding neural development, behavior, and abnormalities of the nervous system. BMP signaling in motor neurons, activated in part by retrograde signals from muscle expressed Gbb (BMP5/6/7) has been implicated in synaptic growth, function and plasticity inDrosophila melanogaster. Through loss-of-function studies, we establish Gbb as a critical mediator of glia to neuron signaling important for proper synaptic growth. Furthermore, the BMP2/4 ortholog, Dpp, expressed in a subset of motor neurons, acts by autocrine signaling to also facilitate neuromuscular junction (NMJ) growth at specific muscle innervation sites. In addition to signaling from glia to motor neurons, autocrine Gbb induces signaling in larval VNC glia which strongly express the BMP type II receptor, Wit. In addition to Dpp’s autocrine motor neuron signaling, Dpp also engages in paracrine signaling to adjacent glia but not to neighboring motor neurons. In one type of dorsal midline motor neuron, RP2,dpptranscription is under tight regulation, as its expression is under autoregulatory control in RP2 but not aCC neurons. Taken together our findings indicate that bi-directional BMP signaling, mediated by two different ligands, facilitates communication between glia and neurons. Gbb, prominently expressed in glia, and Dpp acting from a discrete set of neurons induce active Smad-dependent BMP signaling to influence bouton number during neuromuscular junction growth.

scholarly journals Nemo kinase interacts with Mad to coordinate synaptic growth at the Drosophila neuromuscular junction

2009 ◽  
Vol 185 (4) ◽  
pp. 713-725 ◽  
Author(s):  
Carlos Merino ◽  
Jay Penney ◽  
Miranda González ◽  
Kazuya Tsurudome ◽  
Myriam Moujahidine ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Genetic Interaction ◽  
Phosphorylation Site ◽  
Normal Function ◽  
Bmp Signaling ◽  
Structural Defects ◽  
Synaptic Growth ◽  
N Terminus ◽  
Larval Neuromuscular Junction

Bone morphogenic protein (BMP) signaling is essential for the coordinated assembly of the synapse, but we know little about how BMP signaling is modulated in neurons. Our findings indicate that the Nemo (Nmo) kinase modulates BMP signaling in motor neurons. nmo mutants show synaptic structural defects at the Drosophila melanogaster larval neuromuscular junction, and providing Nmo in motor neurons rescues these defects. We show that Nmo and the BMP transcription factor Mad can be coimmunoprecipitated and find a genetic interaction between nmo and Mad mutants. Moreover, we demonstrate that Nmo is required for normal distribution and accumulation of phosphorylated Mad in motor neurons. Finally, our results indicate that Nmo phosphorylation of Mad at its N terminus, distinct from the BMP phosphorylation site, is required for normal function of Mad. Based on our findings, we propose a model in which phosphorylation of Mad by Nmo ensures normal accumulation and distribution of Mad and thereby fine tunes BMP signaling in motor neurons.

scholarly journals Rgs4 is a regulator of mTOR activity required for motoneuron axon outgrowth and neuronal development in zebrafish

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Mikdache ◽  
Marie-José Boueid ◽  
Lorijn van der Spek ◽  
Emilie Lesport ◽  
Brigitte Delespierre ◽  
...  
Keyword(s):  
Nervous System ◽  
G Protein ◽  
Neural Development ◽  
Neuronal Development ◽  
Axon Outgrowth ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Loss Of Function ◽  
G Protein Coupled

AbstractThe Regulator of G protein signaling 4 (Rgs4) is a member of the RGS proteins superfamily that modulates the activity of G-protein coupled receptors. It is mainly expressed in the nervous system and is linked to several neuronal signaling pathways; however, its role in neural development in vivo remains inconclusive. Here, we generated and characterized a rgs4 loss of function model (MZrgs4) in zebrafish. MZrgs4 embryos showed motility defects and presented reduced head and eye sizes, reflecting defective motoneurons axon outgrowth and a significant decrease in the number of neurons in the central and peripheral nervous system. Forcing the expression of Rgs4 specifically within motoneurons rescued their early defective outgrowth in MZrgs4 embryos, indicating an autonomous role for Rgs4 in motoneurons. We also analyzed the role of Akt, Erk and mechanistic target of rapamycin (mTOR) signaling cascades and showed a requirement for these pathways in motoneurons axon outgrowth and neuronal development. Drawing on pharmacological and rescue experiments in MZrgs4, we provide evidence that Rgs4 facilitates signaling mediated by Akt, Erk and mTOR in order to drive axon outgrowth in motoneurons and regulate neuronal numbers.

scholarly journals Role of BMP receptor traffic in synaptic growth defects in an ALS model

2016 ◽  
Vol 27 (19) ◽  
pp. 2898-2910 ◽  
Author(s):  
Mugdha Deshpande ◽  
Zachary Feiger ◽  
Amanda K. Shilton ◽  
Christina C. Luo ◽  
Ethan Silverman ◽  
...  
Keyword(s):  
Neurological Impairment ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Synaptic Growth ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Bmp Receptor ◽  
Bmp Receptors ◽  
Induced Defects

TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment.

scholarly journals Loss of TBK1 activity leads to TDP-43 proteinopathy through lysosomal dysfunction in human motor neurons

2021 ◽  
Author(s):  
Jin Hao ◽  
Michael F Wells ◽  
Gengle Niu ◽  
Irune Guerra San Juan ◽  
Francesco Limone ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurodegenerative Disease ◽  
Motor Neurons ◽  
Inhibition Mechanism ◽  
Loss Of Function ◽  
Neurodegenerative Process ◽  
Lysosomal Dysfunction ◽  
Human Motor ◽  
Lateral Sclerosis ◽  
Lysosomal Acidification

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss accompanied by cytoplasmic localization of TDP-43 proteins and their insoluble accumulations. Haploinsufficiency of TBK1 has been found to associate with or cause ALS. However, the cell-autonomous mechanisms by which reduced TBK1 activity contributes to human motor neuron pathology remain elusive. Here, we generated a human cellular model harboring loss-of-function mutations of TBK1 by gene editing and found that TBK1 deficiency was sufficient to cause TDP-43 pathology in human motor neurons. In addition to its functions in autophagy, we found that TBK1 interacted with endosomes and was required for normal endosomal maturation and subsequent lysosomal acidification. Surprisingly, TDP-43 pathology resulted more from the dysfunctional endo-lysosomal pathway than the previously recognized autophagy inhibition mechanism. Restoring TBK1 levels ameliorated lysosomal dysfunction and TDP-43 pathology and maintained normal motor neuron homeostasis. Notably, using patient-derived motor neurons, we found that haploinsufficiency of TBK1 sensitized neurons to lysosomal stress, and chemical regulators of endosomal maturation rescued the neurodegenerative process. Together, our results revealed the mechanism of TBK1 in maintaining TDP-43 and motor neuron homeostasis and suggested that modulating endosomal maturation was able to rescue neurodegenerative disease phenotypes caused by TBK1 deficiency.

scholarly journals A three-dimensional culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction and disease modeling

2018 ◽  
Author(s):  
Mohsen Afshar Bakooshli ◽  
Ethan S Lippmann ◽  
Ben Mulcahy ◽  
Nisha R Iyer ◽  
Christine T Nguyen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Human Skeletal Muscle ◽  
Disease Modeling ◽  
De Novo ◽  
Muscle Fibers ◽  
Three Dimensional ◽  
Adult Human

SummaryTwo-dimensional (2D) human skeletal muscle fiber cultures are ill equipped to support the contractile properties of maturing muscle fibers. This limits their application to the study of adult human neuromuscular junction (NMJ) development, a process requiring maturation of muscle fibers in the presence of motor neuron endplates. Here we describe a three-dimensional (3D) co-culture method whereby human muscle progenitors mixed with human pluripotent stem cell-derived motor neurons self-organize to form functional NMJ connections within two weeks. Functional connectivity between motor neuron endplates and muscle fibers is confirmed with calcium transient imaging and electrophysiological recordings. Notably, we only observed epsilon acetylcholine receptor subunit protein upregulation and activity in 3D co-culture. This demonstrates that the 3D co-culture system supports a developmental shift from the embryonic to adult form of the receptor that does not occur in 2D co-culture. Further, 3D co-culture treatments with myasthenia gravis patient sera shows the ease of studying human disease with the system. This work delivers a simple, reproducible, and adaptable method to model and evaluate adult human NMJ de novo development and disease in culture.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4239-4252 ◽  
Author(s):  
S. Hallam ◽  
E. Singer ◽  
D. Waring ◽  
Y. Jin
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Expression Patterns ◽  
Loss Of Function ◽  
Variable Expression ◽  
C Elegans ◽  
Helix Loop Helix ◽  
Ventral Cord ◽  
Bhlh Proteins ◽  
Neuronal Type

The basic helix-loop-helix transcription factor NeuroD (Neurod1) has been implicated in neuronal fate determination, differentiation and survival. Here we report the expression and functional analysis of cnd-1, a C. elegans NeuroD homolog. cnd-1 expression was first detected in neuroblasts of the AB lineage in 14 cell embryos and maintained in many neuronal descendants of the AB lineage during embryogenesis, diminishing in most terminally differentiated neurons prior to hatching. Specifically, cnd-1 reporter genes were expressed in the precursors of the embryonic ventral cord motor neurons and their progeny. A loss-of-function mutant, cnd-1(ju29), exhibited multiple defects in the ventral cord motor neurons. First, the number of motor neurons was reduced, possibly caused by the premature withdrawal of the precursors from mitotic cycles. Second, the strict correlation between the fate of a motor neuron with respect to its lineage and position in the ventral cord was disrupted, as manifested by the variable expression pattern of motor neuron fate specific markers. Third, motor neurons also exhibited defects in terminal differentiation characteristics including axonal morphology and synaptic connectivity. Finally, the expression patterns of three neuronal type-specific transcription factors, unc-3, unc-4 and unc-30, were altered. Our data suggest that cnd-1 may specify the identity of ventral cord motor neurons both by maintaining the mitotic competence of their precursors and by modulating the expression of neuronal type-specific determination factors. cnd-1 appears to have combined the functions of several vertebrate neurogenic bHLH proteins and may represent an ancestral form of this protein family.

Weakness

2018 ◽  
pp. 207-238
Author(s):  
Andrea C. Adams
Keyword(s):  
Nervous System ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor System ◽  
Lower Motor Neuron ◽  
Diagnostic Challenge ◽  
Common Complaint ◽  
Motor Nerves

Weakness is a common complaint. Most patients use the term weakness to imply fatigue, general illness, or myalgias. Determining whether a patient has actual neuromuscular weakness can be a diagnostic challenge. Disease of the motor system can occur at all levels of the nervous system. This chapter considers disorders of the lower motor neuron, including disorders of muscle (myopathies), the neuromuscular junction, and motor nerves.

Dopamine modulation of gill reflex behavior in Aplysia

1979 ◽  
Vol 57 (3) ◽  
pp. 329-332 ◽  
Author(s):  
Peter Ruben ◽  
Ken Lukowiak
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Motor Neuron ◽  
Peripheral Nervous System ◽  
Motor Neurons ◽  
Withdrawal Reflex ◽  
Dopaminergic Pathway ◽  
The Central Nervous System ◽  
Dopamine Modulation

We have studied the effects of dopamine on the gill withdrawal reflex evoked by tactile siphon stimulation in the margine mollusc Aplysia. Physiological concentrations of dopamine (diluted in seawater) were perfused through the gill during siphon stimulation series. The amplitude of the reflex was potentiated by dopamine and habituation of the reflex was prevented. This occurred with no change in the activity evoked in central motor neurons. These results lead us to conclude that the dopaminergic motor neuron L9 is modulating habituation in the periphery and that the central nervous system facilitatory control of the peripheral nervous system may act via a dopaminergic pathway.

Modeling Neuromuscular Modulation in Aplysia. III. Interaction of Central Motor Commands and Peripheral Modulatory State for Optimal Behavior

2005 ◽  
Vol 93 (3) ◽  
pp. 1523-1556 ◽  
Author(s):  
Vladimir Brezina ◽  
Charles C. Horn ◽  
Klaudiusz R. Weiss
Keyword(s):  
Nervous System ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Functional Performance ◽  
Feeding Strategy ◽  
Neuromuscular System ◽  
Robust Performance ◽  
Neuron Firing ◽  
Variable Environment ◽  
Firing Patterns

Recent work in computational neuroethology has emphasized that “the brain has a body”: successful adaptive behavior is not simply commanded by the nervous system, but emerges from interactions of nervous system, body, and environment. Here we continue our study of these issues in the accessory radula closer (ARC) neuromuscular system of Aplysia. The ARC muscle participates in the animal's feeding behaviors, a set of cyclical, rhythmic behaviors driven by a central pattern generator (CPG). Patterned firing of the ARC muscle's two motor neurons, B15 and B16, releases not only ACh to elicit the muscle's contractions but also peptide neuromodulators that then shape the contractions through a complex network of actions on the muscle. These actions are dynamically complex: some are fast, but some are slow, so that they are temporally uncoupled from the motor neuron firing pattern in the current cycle. Under these circumstances, how can the nervous system, through just the narrow channel of the firing patterns of the motor neurons, control the contractions, movements, and behavior in the periphery? In two earlier papers, we developed a realistic mathematical model of the B15/B16-ARC neuromuscular system and its modulation. Here we use this model to study the functional performance of the system in a realistic behavioral task. We run the model with two kinds of inputs: a simple set of regular motor neuron firing patterns that allows us to examine the entire space of patterns, and the real firing patterns of B15 and B16 previously recorded in a 21/2-h-long meal of 749 cycles in an intact feeding animal. These real patterns are extremely irregular. Our main conclusions are the following. 1) The modulation in the periphery is necessary for superior functional performance. 2) The components of the modulatory network interact in nonlinear, context- and task-dependent combinations for best performance overall, although not necessarily in any particular cycle. 3) Both the fast and the slow dynamics of the modulatory state make important contributions. 4) The nervous system controls different components of the periphery to different degrees. To some extent the periphery operates semiautonomously. However, the structure of the peripheral modulatory network ensures robust performance under all circumstances, even with the irregular motor neuron firing patterns and even when the parameters of the functional task are randomly varied from cycle to cycle to simulate a variable feeding environment. In the variable environment, regular firing patterns, which are fine-tuned to one particular task, fail to provide robust performance. We propose that the CPG generates the irregular firing patterns, which nevertheless are guaranteed to give robust performance overall through the actions of the peripheral modulatory network, as part of a trial-and-error feeding strategy in a variable, uncertain environment.

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