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 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 Retrograde BMP Signaling Controls Synaptic Growth at the NMJ by Regulating Trio Expression in Motor Neurons

Neuron ◽  
2010 ◽  
Vol 66 (4) ◽  
pp. 536-549 ◽  
Author(s):  
Robin W. Ball ◽  
Maude Warren-Paquin ◽  
Kazuya Tsurudome ◽  
Edward H. Liao ◽  
Fatima Elazzouzi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Bmp Signaling ◽  
Synaptic Growth

scholarly journals Glial Processes at the Drosophila Larval Neuromuscular Junction Match Synaptic Growth

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37876 ◽  
Author(s):  
Deidre L. Brink ◽  
Mary Gilbert ◽  
Xiaojun Xie ◽  
Lindsay Petley-Ragan ◽  
Vanessa J. Auld
Keyword(s):  
Neuromuscular Junction ◽  
Synaptic Growth ◽  
Larval Neuromuscular Junction

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 The Drosophila TMEM184B ortholog Tmep ensures proper locomotion by restraining ectopic firing at the neuromuscular junction

2021 ◽  
Author(s):  
Tiffany S. Cho ◽  
Eglė Beigaitė ◽  
Nathaniel E. Klein ◽  
Sean T. Sweeney ◽  
Martha R.C. Bhattacharya
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Membrane Trafficking ◽  
Neuromuscular Junctions ◽  
Epileptic Seizures ◽  
Synaptic Activity ◽  
Structural Defects ◽  
Synaptic Membrane ◽  
Critical Function ◽  
Endoplasmic Reticulum Calcium

AbstractTMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes neuromuscular defects is unknown. We employed Drosophila melanogaster to investigate the function of the TMEM184B ortholog, Tmep (CG12004) at the neuromuscular junction. We show that Tmep is required for full adult viability and efficient larval locomotion. Tmep mutant larvae have a reduced body contraction rate compared to controls, with stronger deficits in females. Surviving adult Tmep mutant females show “bang sensitivity,” a phenotype associated with epileptic seizures. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many post-synaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Neuromuscular junctions in Tmep mutants show modest structural defects and satellite boutons, which could also contribute to poor locomotor performance. Tmep is expressed in endosomes and synaptic vesicles within motor neurons, suggesting a possible role in synaptic membrane trafficking. Using RNAi knockdown, we show that Tmep is required in motor neurons for proper larval locomotion and excitability. Locomotor defects can be rescued by presynaptic knock-down of endoplasmic reticulum calcium channels or by reducing evoked release probability, suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for the TMEM184B ortholog Tmep in the regulation of synaptic transmission and locomotor behavior.

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 Nervous Wreck Interacts with Thickveins and the Endocytic Machinery to Attenuate Retrograde BMP Signaling during Synaptic Growth

Neuron ◽  
2008 ◽  
Vol 58 (4) ◽  
pp. 507-518 ◽  
Author(s):  
Kate M. O'Connor-Giles ◽  
Ling Ling Ho ◽  
Barry Ganetzky
Keyword(s):  
Bmp Signaling ◽  
Synaptic Growth ◽  
Endocytic Machinery

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.

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