scholarly journals Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, regulates microtubule dynamics

2020 ◽  
Author(s):  
Mingwei Zhu ◽  
Daniel Martinez ◽  
Jessie J. Guidry ◽  
Niles Majeste ◽  
Hui Mao ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Genetic Interaction ◽  
Function Analysis ◽  
Underlying Mechanism ◽  
Structural Basis ◽  
Synaptic Growth ◽  
Binding Function ◽  
Proteomic Approach ◽  
Kh Domain

AbstractProper regulation of microtubule (MT) dynamics is vital for essential cellular processes and many neuronal activities, including axonal transport and synaptic growth and remodeling. Here we demonstrate that Mask negatively regulates MT stability and maintains a balanced MT length and architecture in both fly larval muscles and motor neurons. In larval muscles, loss of mask increases MT length, and altering mask genetically modifies the Tau-induced MT fragmentation. In motor neurons, loss of mask function reduces the number of End-Binding Protein 1 (EB1)-positive MT plus-ends in the axons and results in overexpansion of the presynaptic terminal at larval neuromuscular junctions (NMJ). mask shows strong genetic interaction with stathmin (stai), a neuronal modulator of MT dynamics, in regulation of axon transportation and synaptic terminal stability. The structure/function analysis on Mask suggests that Mask’s action in regulating MT stability does not depend on the nucleotide-binding function of its KH domain. Furthermore, through a proteomic approach, we found that Mask physically interacts with Jupiter, an MT stabilizing factor. The MT localization of Jupiter in the axons inversely correlates with Mask levels, suggesting that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.Author SummaryMicrotubules (MT) are part of the cytoskeleton of the cells that provides essential structural basis for critical processes and functions of the cells. A complex factors are required to orchestrate the assembly and disassembly of MT. Here we identified Mask as a novel regulator for MT dynamics in fruit flies. Mask negatively regulates MT stability. It shows prominent interplay with two important modulators of MT, Tau and Stathmin (Stai), both genes are linked to human neurodegenerative disorders. These findings not only support the role of Mask as a novel microtubule regulator, but also provide foundation to explore future therapeutic strategies in mitigating deficit related to dysfunction of Tau and Stathmin. Our further analysis on Mask protein demonstrate that Mask can physically interacts with another MT stabilizing factor named Jupiter. Jupiter can bind to MT, but its localization to the MTs in the axons is negatively affected by Mask, implying a possible underlying mechanism that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.

scholarly journals Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, affects microtubule stability

2021 ◽  
Author(s):  
Daniel Martinez ◽  
Mingwei Zhu ◽  
Jessie J. Guidry ◽  
Niles Majeste ◽  
Hui Mao ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Function Analysis ◽  
Normal Function ◽  
Loss Of Function ◽  
Synaptic Growth ◽  
Cellular Processes ◽  
Microtubule Stability ◽  
Kh Domain ◽  
Mask Function

Proper regulation of microtubule (MT) stability and dynamics is vital for essential cellular processes, including axonal transportation and synaptic growth and remodeling in neurons. Here, we demonstrate that Mask negatively affects MT stability in both fly larval muscles and motor neurons. In larval muscles, loss-of-function of mask increases MT polymer length, and in motor neurons, loss of mask function results in overexpansion of the presynaptic terminal at the larval neuromuscular junctions (NMJs). mask genetically interacts with stathmin (stai), a neuronal modulator of MT stability, in the regulation of axon transportation and synaptic terminal stability. Our structure/function analysis on Mask revealed that its Ankyrin Repeats domain-containing N-terminal portion is sufficient to mediate Mask's impact to MT stability. Furthermore, we discovered that Mask negatively regulates the abundance of the microtubule-associated protein Jupiter in motor neuron axons, and that neuronal knocking down of Jupiter partially suppresses mask loss-of-function phenotypes at the larval NMJs. Together, our studies demonstrated that Mask is a novel regulator for microtubule stability, and such a role of Mask requires normal function of Jupiter.

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 The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kathryn P Harris ◽  
Yao V Zhang ◽  
Zachary D Piccioli ◽  
Norbert Perrimon ◽  
J Troy Littleton
Keyword(s):  
Synaptic Plasticity ◽  
Neuromuscular Junctions ◽  
Genetic Interaction ◽  
Retrograde Signaling ◽  
Synaptic Development ◽  
Synaptic Growth ◽  
Adhesion Protein ◽  
Neuronal Stimulation ◽  
Syntaxin 4 ◽  
Activity Dependent

Postsynaptic cells can induce synaptic plasticity through the release of activity-dependent retrograde signals. We previously described a Ca2+-dependent retrograde signaling pathway mediated by postsynaptic Synaptotagmin 4 (Syt4). To identify proteins involved in postsynaptic exocytosis, we conducted a screen for candidates that disrupted trafficking of a pHluorin-tagged Syt4 at Drosophila neuromuscular junctions (NMJs). Here we characterize one candidate, the postsynaptic t-SNARE Syntaxin 4 (Syx4). Analysis of Syx4 mutants reveals that Syx4 mediates retrograde signaling, modulating the membrane levels of Syt4 and the transsynaptic adhesion protein Neuroligin 1 (Nlg1). Syx4-dependent trafficking regulates synaptic development, including controlling synaptic bouton number and the ability to bud new varicosities in response to acute neuronal stimulation. Genetic interaction experiments demonstrate Syx4, Syt4, and Nlg1 regulate synaptic growth and plasticity through both shared and parallel signaling pathways. Our findings suggest a conserved postsynaptic SNARE machinery controls multiple aspects of retrograde signaling and cargo trafficking within the postsynaptic compartment.

Co-Culture of ES Cell-Derived Motor Neurons and Myotubes Show the Formation of Neuromuscular Junctions and Changes in Gene Expression

2006 ◽  
Vol 22 (06) ◽  
Author(s):  
Aleid Ruijs ◽  
Tateki Kubo ◽  
Jae Song ◽  
Milan Ranka ◽  
Mark Randolph ◽  
...  
Keyword(s):  
Gene Expression ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Es Cell

scholarly journals Functional Neuromuscular Junctions Formed by Embryonic Stem Cell-Derived Motor Neurons

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e36049 ◽  
Author(s):  
Joy A. Umbach ◽  
Katrina L. Adams ◽  
Cameron B. Gundersen ◽  
Bennett G. Novitch
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Embryonic Stem

scholarly journals Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity

2018 ◽  
Vol 217 (11) ◽  
pp. 3947-3964 ◽  
Author(s):  
Moushami Mallik ◽  
Marica Catinozzi ◽  
Clemens B. Hug ◽  
Li Zhang ◽  
Marina Wagner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Motor Neurons ◽  
Gene Expression Regulation ◽  
Genetic Interaction ◽  
Motor Deficits ◽  
Chromatin Binding ◽  
Mutant Phenotypes ◽  
Gene Expression Dysregulation ◽  
Lateral Sclerosis

Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.

Craniometric data of Apodemus sylvaticus in Slovakia

Biologia ◽  
2015 ◽  
Vol 70 (7) ◽  
Author(s):  
Alexander Čanády ◽  
Ladislav Mošanský
Keyword(s):  
Discriminant Analysis ◽  
Genetic Interaction ◽  
Function Analysis ◽  
Geographic Distance ◽  
Wood Mouse ◽  
Apodemus Sylvaticus ◽  
Small Scale ◽  
Craniometric Analysis ◽  
North Western ◽  
Different Parts

AbstractA craniometric analysis of skulls of the wood mouse (Apodemus sylvaticus) from three different parts of Slovakia (north-western, northern and south-eastern) was conducted. Twenty-nine skull and dental variables were measured and evaluated on a sample of 56 adult individuals. The overlap of the values of the measured traits was high. Moreover, the differences among the populations were different for each trait. The non-parametric Kruskal-Wallis test and Discriminant function analysis showed variations in the cranial variables among the different parts of country. We have identified six morphometric variables suitable for the differentiation of populations on the basis of discriminant analysis. Significant differences were confirmed in the characteristics between the analyzed regions; thus, we can speak about small-scale craniometric differentiation. In addition, the results could indicate the influence of altitude, even over a shorter geographic distance between 48-49º N. Moreover, restriction of genetic interaction between the populations may in the future lead to even greater differences between the populations in Slovakia.

scholarly journals Myomirnas Role in Als Suggest a Crosstalk between Muscle and Motor Neuron

2018 ◽  
Author(s):  
Valentina Pegoraro ◽  
Antonio Merico ◽  
Corrado Angelini
Keyword(s):  
Skeletal Muscle ◽  
Motor Neuron ◽  
Aerobic Exercise ◽  
Muscle Atrophy ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Muscle Fibres ◽  
Wide Range

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.

Jun mediates Frizzled-induced R3/R4 cell fate distinction and planar polarity determination in the Drosophila eye

Development ◽  
2000 ◽  
Vol 127 (16) ◽  
pp. 3619-3629 ◽  
Author(s):  
U. Weber ◽  
N. Paricio ◽  
M. Mlodzik
Keyword(s):  
Cell Fate ◽  
Genetic Interaction ◽  
Function Analysis ◽  
Loss Of Function ◽  
Planar Polarity ◽  
Jnk Signaling ◽  
Drosophila Eye ◽  
Polarity Determination ◽  
Signaling Components

Jun acts as a signal-regulated transcription factor in many cellular decisions, ranging from stress response to proliferation control and cell fate induction. Genetic interaction studies have suggested that Jun and JNK signaling are involved in Frizzled (Fz)-mediated planar polarity generation in the Drosophila eye. However, simple loss-of-function analysis of JNK signaling components did not show comparable planar polarity defects. To address the role of Jun and JNK in Fz signaling, we have used a combination of loss- and gain-of-function studies. Like Fz, Jun affects the bias between the R3/R4 photoreceptor pair that is critical for ommatidial polarity establishment. Detailed analysis of jun(−) clones reveals defects in R3 induction and planar polarity determination, whereas gain of Jun function induces the R3 fate and associated polarity phenotypes. We find also that affecting the levels of JNK signaling by either reduction or overexpression leads to planar polarity defects. Similarly, hypomorphic allelic combinations and overexpression of the negative JNK regulator Puckered causes planar polarity eye phenotypes, establishing that JNK acts in planar polarity signaling. The observation that Dl transcription in the early R3/R4 precursor cells is deregulated by Jun or Hep/JNKK activation, reminiscent of the effects seen with Fz overexpression, suggests that Jun is one of the transcription factors that mediates the effects of fz in planar polarity generation.

scholarly journals The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Viviana Pérez ◽  
Francisca Bermedo-Garcia ◽  
Diego Zelada ◽  
Felipe A. Court ◽  
Miguel Ángel Pérez ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuronal Damage ◽  
Neuromuscular Synapse ◽  
Force Production ◽  
Synaptic Function ◽  
Neurotrophin Receptor ◽  
Acetylcholinesterase Inhibition ◽  
Pharmacological Intervention

Abstract The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

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