Zebrafish Mecp2 is required for proper axonal elongation of motor neurons and synapse formation

2017 ◽  
Vol 77 (9) ◽  
pp. 1101-1113 ◽  
Author(s):  
Keisuke Nozawa ◽  
Yanbin Lin ◽  
Ryota Kubodera ◽  
Yuki Shimizu ◽  
Hideomi Tanaka ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Synapse Formation ◽  
Axonal Elongation

A Neurexin2aa deficiency results in axon pathfinding defects and increased anxiety in zebrafish

2020 ◽  
Author(s):  
Angela Koh ◽  
Shijie Tao ◽  
Goh Yun Jing ◽  
Vindhya Chaganty ◽  
Kelvin See ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Synapse Formation ◽  
Muscular Atrophy ◽  
Autism Spectrum ◽  
Axon Pathfinding ◽  
Adult Behavior ◽  
Behavioral Studies ◽  
Synapse Maintenance ◽  
A Cell ◽  
Induced Defects

Abstract Neurexins are presynaptic transmembrane proteins that control synapse activity and are risk factors for autism spectrum disorder (ASD). Zebrafish, a popular model for behavioral studies, has six neurexin genes, but their functions in embryogenesis and behavior remain largely unknown. We have previously reported that nrxn2a is aberrantly spliced and specifically dysregulated in motor neurons (MNs) in models of Spinal Muscular Atrophy (SMA). In this study, we generated nrxn2aa−/− mutants by CRISPR/Cas9 to understand nrxn2aa function at the zebrafish neuromuscular junction (NMJ) and to determine the effects of its deficiency on adult behavior. Homozygous mutant embryos derived from heterozygous parents did not show obvious defects in axon outgrowth or synaptogenesis of MNs. In contrast, maternal-zygotic (MZ) nrxn2aa−/− mutants displayed extensively branched axons and defective MNs, suggesting a cell-autonomous role for maternally provided nrxn2aa in MN development. Analysis of the NMJs revealed enlarged choice points in MNs of mutant larvae and reduced co-localization of pre- and post-synaptic terminals, indicating impaired synapse formation. Severe early NMJ defects partially recovered in late embryos when mutant transcripts became strongly upregulated. Ultimately, however, the induced defects result in muscular atrophy symptoms in adult MZ mutants. Zygotic homozygous mutants developed normally but displayed increased anxiety at adult stages. Together, our data demonstrate an essential role for maternal nrxn2aa in NMJ synapse establishment, while zygotic nrxn2aa expression appears dispensable for synapse maintenance. The viable nrxn2aa−/− mutant furthermore serves as a novel model to study how an increase in anxiety-like behaviors impacts other deficits.

scholarly journals Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sangmok Kim ◽  
Kelsey C Martin
Keyword(s):  
Motor Neurons ◽  
Synapse Formation ◽  
Synaptic Contact ◽  
Brain Connectivity ◽  
Rna Localization ◽  
Local Translation ◽  
Rna Transport ◽  
Calcium Dependent ◽  
And Function ◽  
Local Stimulation

The persistence of experience-dependent changes in brain connectivity requires RNA localization and protein synthesis. Previous studies have demonstrated a role for local translation in altering the structure and function of synapses during synapse formation and experience-dependent synaptic plasticity. In this study, we ask whether in addition to promoting local translation, local stimulation also triggers directed trafficking of RNAs from nucleus to stimulated synapses. Imaging of RNA localization and translation in cultured Aplysia sensory-motor neurons revealed that RNAs were delivered throughout the arbor of the sensory neuron, but that translation was enriched only at sites of synaptic contact and/or synaptic stimulation. Investigation of the mechanisms that trigger local translation revealed a role for calcium-dependent retrograde netrin-1/DCC receptor signaling. Spatially restricting gene expression by regulating local translation rather than by directing the delivery of mRNAs from nucleus to stimulated synapses maximizes the readiness of the entire neuronal arbor to respond to local cues.

scholarly journals Neuron–glia interactions: the roles of Schwann cells in neuromuscular synapse formation and function

2011 ◽  
Vol 31 (5) ◽  
pp. 295-302 ◽  
Author(s):  
Yoshie Sugiura ◽  
Weichun Lin
Keyword(s):  
Schwann Cells ◽  
Motor Neurons ◽  
Nerve Terminal ◽  
Synapse Formation ◽  
Neuromuscular Synapse ◽  
Synaptic Activity ◽  
Nerve Terminals ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Nerve Terminals ◽  
And Function

The NMJ (neuromuscular junction) serves as the ultimate output of the motor neurons. The NMJ is composed of a presynaptic nerve terminal, a postsynaptic muscle and perisynaptic glial cells. Emerging evidence has also demonstrated an existence of perisynaptic fibroblast-like cells at the NMJ. In this review, we discuss the importance of Schwann cells, the glial component of the NMJ, in the formation and function of the NMJ. During development, Schwann cells are closely associated with presynaptic nerve terminals and are required for the maintenance of the developing NMJ. After the establishment of the NMJ, Schwann cells actively modulate synaptic activity. Schwann cells also play critical roles in regeneration of the NMJ after nerve injury. Thus, Schwann cells are indispensable for formation and function of the NMJ. Further examination of the interplay among Schwann cells, the nerve and the muscle will provide insights into a better understanding of mechanisms underlying neuromuscular synapse formation and function.

scholarly journals Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Éric Martineau ◽  
Adriana Di Polo ◽  
Christine Vande Velde ◽  
Richard Robitaille
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Axonal Degeneration ◽  
Synapse Formation ◽  
Neuromuscular Junctions ◽  
Motor Units ◽  
Early Event ◽  
Motor Neuron Degeneration ◽  
Single Motor Units

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

scholarly journals Kinesin-3 mediated delivery of presynaptic neurexin stabilizes growing dendritic spines and postsynaptic components in vivo

2021 ◽  
Author(s):  
Devyn Oliver ◽  
Shankar Ramachandran ◽  
Alison Philbrook ◽  
Christopher M Lambert ◽  
Ken C. Q. Nguyen ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Synaptic Activity ◽  
Presynaptic Terminals ◽  
Adhesion Protein ◽  
C Elegans ◽  
Specific Regulation ◽  
Receptor Clusters

A high degree of cell and circuit-specific regulation has complicated efforts to precisely define roles for synaptic adhesion proteins in establishing circuit connectivity. Here, we take advantage of the strengths of C. elegans for cell-specific analyses to investigate molecular coordination of pre- and postsynaptic development. We show that developing dendritic spines emerge from the dendrites of wild type GABAergic motor neurons following the localization of active zone proteins and the formation of immature synaptic vesicle assemblies in presynaptic terminals. Similarly, clusters of postsynaptic receptors and F-actin are visible in GABAergic dendrites prior to spine outgrowth. Surprisingly, these developmental processes occur without a requirement for synaptic activity. Likewise, the initial stages of spine outgrowth and receptor clustering are not altered by deletion of the C. elegans ortholog of the transsynaptic adhesion protein, neurexin/NRX-1. Over time, however, dendritic spines and postsynaptic receptor clusters are destabilized in the absence of presynaptic NRX-1/neurexin and collapse prior to adulthood. The kinesin-3 family member, UNC-104, delivers NRX-1 to presynaptic terminals and ongoing UNC-104 delivery is required into adulthood for the maintenance of postsynaptic structure. Our findings provide novel insights into the temporal order of synapse formation events in vivo and demonstrate a requirement for transsynaptic adhesion in stabilizing mature circuit connectivity.

scholarly journals How prolonged expression of Hunchback, a temporal transcription factor, re-wires locomotor circuits

2019 ◽  
Author(s):  
Julia L. Meng ◽  
Zarion D. Marshall ◽  
Meike Lobb-Rabe ◽  
Ellie S. Heckscher
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Synapse Formation ◽  
Target Selection ◽  
Neuromuscular Synapse ◽  
Biomedical Intervention ◽  
Neuronal Stem Cell ◽  
Dendrite Morphogenesis

Abstract:In many CNS regions, neuronal birth timing is associated with circuit membership. In Drosophila larvae, we show U motor neurons are a temporal cohort—a set of non-identical, contiguously-born neurons from a single neuronal stem cell that contribute to the same circuit. We prolong expression of a temporal transcription factor, Hunchback, to increase the number of U motor neurons with early-born molecular identities. On the circuit level, this expands and re-wires the U motor neuron temporal cohort. On the cell biological level, we find novel roles for Hunchback in motor neuron target selection, neuromuscular synapse formation, dendrite morphogenesis, and behavior. These data provide insight into the relationship between stem cell and circuit, show that Hunchback is a potent regulator of circuit assembly, and suggest that temporal transcription factors are molecules that could be altered during evolution or biomedical intervention for the generation of novel circuits.

Regulation of central neuron synaptic targeting by the Drosophila POU protein, Acj6

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2395-2405
Author(s):  
S.J. Certel ◽  
P.J. Clyne ◽  
J.R. Carlson ◽  
W.A. Johnson
Keyword(s):  
Motor Neurons ◽  
Synapse Formation ◽  
Target Selection ◽  
Adult Brain ◽  
Synaptic Targeting ◽  
Amino Terminal ◽  
Pou Domain ◽  
Alternatively Spliced ◽  
The Central Nervous System ◽  
Class Iv

Mutations in the Drosophila class IV POU domain gene, abnormal chemosensory jump 6 (acj6), have previously been shown to cause physiological deficits in odor sensitivity. However, loss of Acj6 function also has a severe detrimental effect upon coordinated larval and adult movement that cannot be explained by the simple loss in odorant detection. In addition to olfactory sensory neurons, Acj6 is expressed in a distinct subset of postmitotic interneurons in the central nervous system from late embryonic to adult stages. In the larval and adult brain, Acj6 is highly expressed in central brain, optic and antennal lobe neurons. Loss of Acj6 function in larval optic lobe neurons results in disorganized retinal axon targeting and synapse selection. Furthermore, the lamina neurons themselves exhibit disorganized synaptic arbors in the medulla of acj6 mutant pupal brains, suggesting that Acj6 may play a role in regulating synaptic connections or structure. To further test this hypothesis, we misexpressed two Acj6 isoforms in motor neurons where they are not normally found. The two Acj6 isoforms are produced from alternatively spliced acj6 transcripts, resulting in significant structural differences in the amino-terminal POU IV box. Acj6 misexpression caused marked alterations at the neuromuscular junction, with contrasting effects upon nerve terminal branching and synapse formation associated with specific Acj6 isoforms. Our results suggest that the class IV POU domain factor, Acj6, may play an important role in regulating synaptic target selection by central neurons and that the amino-terminal POU IV box is important for regulation of Acj6 activity.

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