scholarly journals Gradient-independent Wnt signaling instructs asymmetric neurite pruning in C. elegans

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Menghao Lu ◽  
Kota Mizumoto
Keyword(s):  
Nervous System ◽  
Motor Neuron ◽  
Wnt Signaling ◽  
The Novel ◽  
Developmentally Regulated ◽  
C Elegans ◽  
Refinement Process ◽  
Excess Number

During development, the nervous system undergoes a refinement process by which neurons initially extend an excess number of neurites, the majority of which will be eliminated by the mechanism called neurite pruning. Some neurites undergo stereotyped and developmentally regulated pruning. However, the signaling cues that instruct stereotyped neurite pruning are yet to be fully elucidated. Here we show that Wnt morphogen instructs stereotyped neurite pruning for proper neurite projection patterning of the cholinergic motor neuron called PDB in C. elegans. In lin-44/wnt and lin-17/frizzled mutant animals, the PDB neurites often failed to prune and grew towards the lin-44-expressing cells. Surprisingly, membrane-tethered lin-44 is sufficient to induce proper neurite pruning in PDB, suggesting that neurite pruning does not require a Wnt gradient. LIN-17 and DSH-1/Dishevelled proteins were recruited to the pruning neurites in lin-44-dependent manners. Our results revealed the novel gradient-independent role of Wnt signaling in instructing neurite pruning.

scholarly journals Gradient-independent Wnt signaling instructs asymmetric neurite pruning in C. elegans

2019 ◽  
Author(s):  
Menghao Lu ◽  
Kota Mizumoto
Keyword(s):  
Nervous System ◽  
Motor Neuron ◽  
Wnt Signaling ◽  
The Novel ◽  
Developmentally Regulated ◽  
C Elegans ◽  
Refinement Process ◽  
Excess Number

AbstractDuring development, the nervous system undergoes refinement process by which neurons initially extend an excess number of neurites, the majority of which will be eliminated by the mechanism called neurite pruning. Some neurites undergo stereotyped and developmentally regulated pruning. However, the signaling cues that instruct stereotyped neurite pruning are yet to be fully elucidated. Here we show that Wnt morphogen instructs stereotyped neurite pruning for proper neurite projection patterning of the cholinergic motor neuron called PDB in C. elegans. In the loss of lin-44/wnt and lin-17/frizzled mutant animals, the PDB neurites often failed to prune and grew towards the lin-44-expressing cells. Surprisingly, membrane-tethered lin-44 is sufficient to induce proper neurite pruning in PDB, suggesting that neurite pruning does not require Wnt gradient. LIN-17 and DSH-1/Dishevelled proteins were recruited to the pruning neurites in lin-44-dependent manners. Our results revealed the novel gradient-independent role of Wnt signaling in instructing neurite pruning.

scholarly journals Roles of Drosophila Hox Genes in the Assembly of Neuromuscular Networks and Behavior

2022 ◽  
Vol 9 ◽  
Author(s):  
Rohit Joshi ◽  
Rashmi Sipani ◽  
Asif Bakshi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Motor Neuron ◽  
Hox Genes ◽  
Neural Circuitry ◽  
Neuron Morphology ◽  
Developing Region ◽  
And Behavior ◽  
Anterior Posterior

Hox genes have been known for specifying the anterior-posterior axis (AP) in bilaterian body plans. Studies in vertebrates have shown their importance in developing region-specific neural circuitry and diversifying motor neuron pools. In Drosophila, they are instrumental for segment-specific neurogenesis and myogenesis early in development. Their robust expression in differentiated neurons implied their role in assembling region-specific neuromuscular networks. In the last decade, studies in Drosophila have unequivocally established that Hox genes go beyond their conventional functions of generating cellular diversity along the AP axis of the developing central nervous system. These roles range from establishing and maintaining the neuromuscular networks to controlling their function by regulating the motor neuron morphology and neurophysiology, thereby directly impacting the behavior. Here we summarize the limited knowledge on the role of Drosophila Hox genes in the assembly of region-specific neuromuscular networks and their effect on associated behavior.

scholarly journals Novel Technological Advances in Functional Connectomics in C. elegans

2019 ◽  
Vol 7 (2) ◽  
pp. 8 ◽  
Author(s):  
DiLoreto ◽  
Chute ◽  
Bryce ◽  
Srinivasan
Keyword(s):  
Nervous System ◽  
Computational Modeling ◽  
Activity Patterns ◽  
Sensory Information ◽  
Neuronal Cell ◽  
Network Models ◽  
Connectivity Matrix ◽  
C Elegans ◽  
Technological Advances

The complete structure and connectivity of the Caenorhabditis elegans nervous system (“mind of a worm”) was first published in 1986, representing a critical milestone in the field of connectomics. The reconstruction of the nervous system (connectome) at the level of synapses provided a unique perspective of understanding how behavior can be coded within the nervous system. The following decades have seen the development of technologies that help understand how neural activity patterns are connected to behavior and modulated by sensory input. Investigations on the developmental origins of the connectome highlight the importance of role of neuronal cell lineages in the final connectivity matrix of the nervous system. Computational modeling of neuronal dynamics not only helps reconstruct the biophysical properties of individual neurons but also allows for subsequent reconstruction of whole-organism neuronal network models. Hence, combining experimental datasets with theoretical modeling of neurons generates a better understanding of organismal behavior. This review discusses some recent technological advances used to analyze and perturb whole-organism neuronal function along with developments in computational modeling, which allows for interrogation of both local and global neural circuits, leading to different behaviors. Combining these approaches will shed light into how neural networks process sensory information to generate the appropriate behavioral output, providing a complete understanding of the worm nervous system.

scholarly journals Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity

2019 ◽  
Vol 7 (3) ◽  
pp. 17 ◽  
Author(s):  
Devyn Oliver ◽  
Emily Norman ◽  
Heather Bates ◽  
Rachel Avard ◽  
Monika Rettler ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuron Development ◽  
Wild Type ◽  
Cell Type ◽  
C Elegans ◽  
Cell Type Specific ◽  
Two Phases

Formation of the nervous system requires a complex series of events including proper extension and guidance of neuronal axons and dendrites. Here we investigate the requirement for integrins, a class of transmembrane cell adhesion receptors, in regulating these processes across classes of C. elegans motor neurons. We show α integrin/ina-1 is expressed by both GABAergic and cholinergic motor neurons. Despite this, our analysis of hypomorphic ina-1(gm144) mutants indicates preferential involvement of α integrin/ina-1 in GABAergic commissural development, without obvious involvement in cholinergic commissural development. The defects in GABAergic commissures of ina-1(gm144) mutants included both premature termination and guidance errors and were reversed by expression of wild type ina-1 under control of the native ina-1 promoter. Our results also show that α integrin/ina-1 is important for proper outgrowth and guidance of commissures from both embryonic and post-embryonic born GABAergic motor neurons, indicating an ongoing requirement for integrin through two phases of GABAergic neuron development. Our findings provide insights into neuron-specific roles for integrin that would not be predicted based solely upon expression analysis.

scholarly journals Synthetic ablations in the C. elegans nervous system

2020 ◽  
Vol 4 (1) ◽  
pp. 200-216 ◽  
Author(s):  
Emma K. Towlson ◽  
Albert-László Barabási
Keyword(s):  
Nervous System ◽  
Synthetic Lethality ◽  
Neural System ◽  
Network Control ◽  
Loss Of Control ◽  
C Elegans ◽  
Touch Response ◽  
Systematic Framework ◽  
Systematic Knowledge

Synthetic lethality, the finding that the simultaneous knockout of two or more individually nonessential genes leads to cell or organism death, has offered a systematic framework to explore cellular function, and also offered therapeutic applications. Yet the concept lacks its parallel in neuroscience—a systematic knowledge base on the role of double or higher order ablations in the functioning of a neural system. Here, we use the framework of network control to systematically predict the effects of ablating neuron pairs and triplets on the gentle touch response. We find that surprisingly small sets of 58 pairs and 46 triplets can reduce muscle controllability in this context, and that these sets are localized in the nervous system in distinct groups. Further, they lead to highly specific experimentally testable predictions about mechanisms of loss of control, and which muscle cells are expected to experience this loss.

Role of Wnt Signaling in Central Nervous System Injury

2015 ◽  
Vol 53 (4) ◽  
pp. 2297-2311 ◽  
Author(s):  
Catherine Lambert ◽  
Pedro Cisternas ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Wnt Signaling ◽  
Central Nervous System Injury

scholarly journals Neuroligin dependence of pharyngeal pumping reveals an extrapharyngeal modulation of Caenorhabditis elegans feeding

2018 ◽  
Author(s):  
Fernando Calahorro ◽  
Francesca Keefe ◽  
James Dillon ◽  
Lindy Holden-Dye ◽  
Vincent O’Connor
Keyword(s):  
Decision Making ◽  
Nervous System ◽  
Body Wall ◽  
Neural Circuits ◽  
Orthologous Gene ◽  
Sensory Cues ◽  
C Elegans ◽  
Sensory Modalities ◽  
Pharyngeal Pumping

ABSTRACTThe integration of distinct sensory modalities is essential for behavioural decision making. In C. elegans this process is coordinated by neural circuits that integrate sensory cues from the environment to generate an appropriate behaviour at the appropriate output muscles. Food is a multimodal cue that impacts on the microcircuits to modulating feeding and foraging drivers at the level of the pharyngeal and body wall muscle respectively. When food triggers an upregulation in pharyngeal pumping it allows the effective ingestion of food. Here we show that a C. elegans mutant in the single orthologous gene of human neuroligins, nlg-1 are defective in food induced pumping. This is not explained by an inability to sense food, as nlg-1 mutants are not defective in chemotaxis towards bacteria. In addition, we show that neuroligin is widely expressed in the nervous system including AIY, ADE, ALA, URX and HSN neurones. Interestingly, despite the deficit in pharyngeal pumping neuroligin is not expressed within the pharyngeal neuromuscular network, which suggests an extrapharyngeal regulation of this circuit. We resolve electrophysiologically the neuroligin contribution to the pharyngeal circuit by mimicking a food-dependent pumping, and show that the nlg-1 phenotype is similar to mutants impaired in GABAergic and/or glutamatergic signalling. We suggest that neuroligin organizes extrapharyngeal circuits that regulate the pharynx. These observations based on the molecular and cellular determinants of feeding are consistent with the emerging role of neuroligin in discretely impacting functional circuits underpinning complex behaviours.

scholarly journals The conserved ASCL1/MASH-1 ortholog HLH-3 specifies sex-specific ventral cord motor neuron fate in C. elegans

2020 ◽  
Author(s):  
Lillian M. Perez ◽  
Aixa Alfonso
Keyword(s):  
Motor Neuron ◽  
Cell Fate ◽  
Motor Neurons ◽  
Bhlh Protein ◽  
Differentiation Markers ◽  
C Elegans ◽  
Ventral Cord ◽  
Neural Specification

ABSTRACTNeural specification can be regulated by one or many transcription factors. Here we identify a novel role for one conserved proneural factor, the bHLH protein HLH-3, implicated in the specification of sex-specific ventral cord motor neurons in C. elegans. In the process of characterizing the role of hlh-3 in neural specification, we document that differentiation of the ventral cord type C neurons, VCs, within their motor neuron class, is dynamic in time and space. Expression of VC class-specific and subclass-specific identity genes is distinct through development and dependent on where they are along the A-P axis (and their position in proximity to the vulva). Our characterization of the expression of VC class and VC subclass-specific differentiation markers in the absence of hlh-3 function reveals that VC fate specification, differentiation, and morphology requires hlh-3 function. Finally, we conclude that hlh-3 cell-autonomously specifies VC cell fate.

Role of Androgen Dependent TFPI-Regulating Protein (ADTRP) in Vascular Development and Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 556-556 ◽  
Author(s):  
Maulin Mukeshchandra Patel ◽  
Robert Silasi-Mansat ◽  
Ravi Shankar Keshari ◽  
Christopher L. Sansam ◽  
David A. Jones ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Target Genes ◽  
Vascular Development ◽  
The Novel ◽  
Canonical Wnt Signaling ◽  
And Function ◽  
Canonical Wnt

Abstract We used in vitro and in vivo models to characterize the physiological role of the novel protein encoded by C6ORF105. This gene's expression is androgen-responsive, and the encoded protein is predicted to be palmitoylated and membrane multi-spanning. Previously we showed that C6ORF105 expression co-regulates with tissue factor pathway inhibitor (TFPI)in human endothelial cells (EC); hence we named this protein "androgen-dependent TFPI-regulating protein" (ADTRP). Using in vitro cell-based TOP-Flash reporter assay we identified ADTRP as a negative regulator of canonical Wnt signaling in human cells. Overexpressing ADTRP in HEK293T cells inhibited the activity of beta-catenin/TCF-dependent transcriptional reporter, while silencing ADTRP increased the expression of Wnt target genes LEF-1, AXIN-2, IL-8 and DKK-2 in EA.hy926 EC line and HUVEC. Addition of LiCl showed that the effect of ADTRP was upstream of GSK3, therefore we focused the investigations on the Wnt signalosome proteins. ADTRP expression in HEK293T cells led to decreased phosphorylation of Wnt co-receptor LRP6, suggesting that ADTRP can affect this critical membrane-located event of Wnt signaling. Furthermore, ADTRP expression in reporter cells transfected with a constitutively phosphorylated form of LRP6 (LRP6DN mutant) inhibited Wnt3a- induced signaling, which suggests that ADTRP can interfere with events downstream of LRP6 phosphorylation, such as Axin-2 binding. Altogether, these data indicate that the Wnt signaling inhibitory activity of ADTRP takes place at the plasma membrane level. Site directed mutagenesis of the predicted palmitoylation site Cys61 showed that Wnt inhibitory effects of ADTRP require palmitoyl-mediated anchoring, highlighting the importance of proper membrane location of ADTRP for Wnt pathway inhibition. In vivo morpholino-based knockdown of adtrp in zebrafish embryos produced aberrant angiogenesis, defective branching and ruptured vessels, hemorrhage spots, pericardial edema and slow heart-beat, all reminiscent of defects caused by activation of canonical Wnt signaling. Indeed, adtrp knock down increased Wnt mediated lef-1 and pax-2a as well as mmp2 and mmp9 mRNA expression. Co-injection of ADTRP mRNA partially recovered the adtrp morpholino- induced morphologic abnormalities. Also, knock down of adtrp in a Wnt reporter zebrafish showed increased expression of ectopic Wnt signaling. Furthermore, our recently established Adtrp-/- mice also display some typical Wnt-mediated vascular defects, including: (i) abnormal patterning, increased capillary tortuosity, abnormal branching and increased density of the capillary network; (ii) dilated vessels, especially venules and veins; (iii) increased leakeage of permeability tracers (Evans blue and fluorescent dextran) without evident changes in endothelial junctions; (iv) hemorrhage spots in the skin, meningeal layers, heart, bladder and kidneys; (v) intravascular and interstitial fibrin deposition in the lung, liver and kidney. ADTRP deficiency decreased plasma TFPI antigen by ~2-times. Furthermore, TFPI antigen and anticoagulant activity in lung extracts and isolated lung EC were similarly decreased, which confirms our previous in vitro data. We aslo noticed increased tail bleeding time (>500 sec vs. 200 sec in WT littermates) and blood volume loss, which likely was caused by increased dilation of the tail vein. Gene expression analysis of whole organs showed upregulation of Wnt target genes involved in vascular contractility (Nos3), and extracellular matrix remodeling (Mmp2). Similarly, skin fibroblasts and lung EC isolated from Adtrp-/- mice showed increased expression of Wnt target genes (Lef-1, Cyclin D, Dkk2, c-Myc), which indicates constitutive activation of canonical Wnt signaling. In conclusion, we used genetic animal models and cell culture systems to show for the first time that the novel protein ADTRP plays major roles in vascular development and function. Lack of, or low levels of ADTRP associate with activation of coagulation and vascular development defects, which may be due, at least in part, to intrinsic high levels of ectopic canonical Wnt signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals Revisiting the role of mitochondria in spinal muscular atrophy

2021 ◽  
Author(s):  
Rachel James ◽  
Helena Chaytow ◽  
Leire M. Ledahawsky ◽  
Thomas H. Gillingwater
Keyword(s):  
Nervous System ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Neurodegenerative Disorders ◽  
Autosomal Recessive ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Clinical Severity ◽  
Motor Neuron Diseases

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor neuron 1 (SMN1) gene. Despite its name, SMN is a ubiquitous protein that functions within and outside the nervous system and has multiple cellular roles in transcription, translation, and proteostatic mechanisms. Encouragingly, several SMN-directed therapies have recently reached the clinic, albeit this has highlighted the increasing need to develop combinatorial therapies for SMA to achieve full clinical efficacy. As a subcellular site of dysfunction in SMA, mitochondria represents a relevant target for a combinatorial therapy. Accordingly, we will discuss our current understanding of mitochondrial dysfunction in SMA, highlighting mitochondrial-based pathways that offer further mechanistic insights into the involvement of mitochondria in SMA. This may ultimately facilitate translational development of targeted mitochondrial therapies for SMA. Due to clinical and mechanistic overlaps, such strategies may also benefit other motor neuron diseases and related neurodegenerative disorders.

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