Opposing roles of PlexinA and PlexinB in axonal branch and varicosity formation

Neufeld, Shay Q; Hibbert, Alexa D; Chen, Brian E.

doi:10.1186/1756-6606-4-15

Cited by 7 publications

(13 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we use the larval NMJ to examine the interaction between the plexin-semaphorin components and mutant GlyRS toxicity. However, unravelling the complete contribution of plexin-semaphorin signaling to CMT2D, in both the peripheral and central nervous systems, is made difficult by the complexity of the temporally and spatially diverse functions mediated through both plexin types (Neufeld et al, 2011 ; Roh et al, 2016 ). For example, Drosophila PlexA has been shown to drive repulsive axon guidance cues in the embryo, whilst PlexB can initiate either repulsive or attractive cell-cell interactions depending on the cellular environment (Winberg et al, 1998 ; Berke and Keshishian, 2011 ; Wu et al, 2011 ; Jeong et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy

Grice

Sleigh

Cader

2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Dominant mutations in GARS, encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ). In this Drosophila model for CMT2D, we have previously shown that mutant gars expression decreases viability and larval motor function, and causes a concurrent build-up of mutant GlyRS at the larval neuromuscular presynapse. Here, we report additional phenotypes that closely mimic the axonal branching defects of Drosophila plexin transmembrane receptor mutants, implying interference of plexin signaling in gars mutants. Individual dosage reduction of two Drosophila Plexins, plexin A (plexA) and B (plexB) enhances and represses the viability and larval motor defects caused by mutant GlyRS, respectively. However, we find plexB levels, but not plexA levels, modify mutant GlyRS association with the presynaptic membrane. Furthermore, increasing availability of the plexB ligand, Semaphorin-2a (Sema2a), alleviates the pathology and the build-up of mutant GlyRS, suggesting competition for plexB binding may be occurring between these two ligands. This toxic gain-of-function and subversion of neurodevelopmental processes indicate that signaling pathways governing axonal guidance could be integral to neuropathology and may underlie the non-cell autonomous CMT2D mechanism.

show abstract

Section: Discussionmentioning

confidence: 99%

Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy

Grice

Sleigh

Cader

2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Recently, Plexin A receptor function has also been shown to act specifically in shaping axonal branching morphology of Drosophila mechanosensory neurons [40]. There, RNAi mediated reduction of plexinA increased the axonal arbor complexity by increasing branch length and the total number of branches, without an apparent change in branch location.…”

Section: Discussionmentioning

confidence: 99%

Plexin A3 and Turnout Regulate Motor Axonal Branch Morphogenesis in Zebrafish

Sainath

Granato

2013

PLoS ONE

View full text Add to dashboard Cite

During embryogenesis motor axons navigate to their target muscles, where individual motor axons develop complex branch morphologies. The mechanisms that control axonal branching morphogenesis have been studied intensively, yet it still remains unclear when branches begin to form or how branch locations are determined. Live cell imaging of individual zebrafish motor axons reveals that the first axonal branches are generated at the ventral extent of the myotome via bifurcation of the growth cone. Subsequent branches are generated by collateral branching restricted to their synaptic target field along the distal portion of the axon. This precisely timed and spatially restricted branching process is disrupted in turnout mutants we identified in a forward genetic screen. Molecular genetic mapping positioned the turnout mutation within a 300 kb region encompassing eight annotated genes, however sequence analysis of all eight open reading frames failed to unambiguously identify the turnout mutation. Chimeric analysis and single cell labeling reveal that turnout function is required cell non-autonomously for intraspinal motor axon guidance and peripheral branch formation. turnout mutant motor axons form the first branch on time via growth cone bifurcation, but unlike wild-type they form collateral branches precociously, when the growth cone is still navigating towards the ventral myotome. These precocious collateral branches emerge along the proximal region of the axon shaft typically devoid of branches, and they develop into stable, permanent branches. Furthermore, we find that null mutants of the guidance receptor plexin A3 display identical motor axon branching defects, and time lapse analysis reveals that precocious branch formation in turnout and plexin A3 mutants is due to increased stability of otherwise short-lived axonal protrusions. Thus, plexin A3 dependent intrinsic and turnout dependent extrinsic mechanisms suppress collateral branch morphogenesis by destabilizing membrane protrusions before the growth cone completes navigation into the synaptic target field.

show abstract

“…Dual color dye labeling of scutellar neurons and unaffected dorsocentral neurons were performed periodically to ensure specificity of the Gal4 driver 16 , and 455-Gal4>Dscam dsRNA flies, which lack all axonal branch targeting, were used as negative controls 15,16 . Experiments were performed on two day old female flies with the experimenter blind to genotype.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

et al. 2013

Self Cite

View full text Add to dashboard Cite

Fragile X syndrome is caused by loss of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein that suppresses protein translation. Here, we identified Down Syndrome Cell Adhesion Molecule (Dscam) RNA, a molecule involved in neural development and implicated in Down syndrome, bound to FMRP. Elevated Dscam protein levels in Drosophila FMRP null animals and in animals with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit which impaired the animal’s sensory perception. Reducing Dscam levels in FMRP null animals reduced synaptic targeting errors and rescued behavioral responses. Our results demonstrate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in major causes of intellectual disability.

show abstract

Opposing roles of PlexinA and PlexinB in axonal branch and varicosity formation

Cited by 7 publications

References 40 publications

Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy

Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy

Plexin A3 and Turnout Regulate Motor Axonal Branch Morphogenesis in Zebrafish

Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

Contact Info

Product

Resources

About