Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release

Neurotransmission is mediated by synaptic exocytosis of neuropeptide-containing dense-core vesicles (DCVs) and small-molecule transmitter-containing small synaptic vesicles (SSVs). Exocytosis of both vesicle types depends on Ca2+ and shared secretory proteins. Here, we show that increasing or decreasing expression of Myopic (mop, HD-PTP, PTPN23), a Bro1 domain-containing pseudophosphatase implicated in neuronal development and neuropeptide gene expression, increases synaptic neuropeptide stores at the Drosophila neuromuscular junction (NMJ). This occurs without altering DCV content or transport, but synaptic DCV number and age are increased. The effect on synaptic neuropeptide stores is accounted for by inhibition of activity-induced Ca2+-dependent neuropeptide release. cAMP-evoked Ca2+-independent synaptic neuropeptide release also requires optimal Myopic expression, showing that Myopic affects the DCV secretory machinery shared by cAMP and Ca2+ pathways. Presynaptic Myopic is abundant at early endosomes, but interaction with the endosomal sorting complex required for transport III (ESCRT III) protein (CHMP4/Shrub) that mediates Myopic’s effect on neuron pruning is not required for control of neuropeptide release. Remarkably, in contrast to the effect on DCVs, Myopic does not affect release from SSVs. Therefore, Myopic selectively regulates synaptic DCV exocytosis that mediates peptidergic transmission at the NMJ.

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Retrieved constituents of large dense-cored vesicles and synaptic vesicles intermix in stimulation-induced early endosomes of noradrenergic neurons

Journal of Cell Science ◽

10.1242/jcs.111.6.681 ◽

1998 ◽

Vol 111 (6) ◽

pp. 681-689 ◽

Cited By ~ 1

Author(s):

P. Partoens ◽

D. Slembrouck ◽

J. Quatacker ◽

P. Baudhuin ◽

P.J. Courtoy ◽

...

Keyword(s):

Synaptic Vesicles ◽

Gradient Centrifugation ◽

Sucrose Density Gradient ◽

Noradrenergic Neurons ◽

Sucrose Density Gradient Centrifugation ◽

Endosomal Sorting ◽

Early Endosomes ◽

Cervical Ganglion ◽

Electron Lucent ◽

Fetal Pig

Two storage compartments in cultured noradrenergic neurons derived from the superior cervical ganglion from fetal pig have been defined using sucrose density gradient centrifugation and electron microscopy: (1) large dense-cored vesicles (LDV) contain noradrenaline and dopamine-beta-hydroxylase (DbetaH); (2) small electron-lucent vesicles contain acetylcholine and p38 and represent the noradrenergic small synaptic vesicles (SSV); no small dense-cored vesicles (SDV) could be detected. Our results demonstrate that internalized LDV membrane constituents are retrieved into early endosomes, as shown by the colocalization of retrieved DbetaH with the endosomal markers Rab5 and HRP in sucrose density gradients and on confocal microscopical images. Recycling of the SSV membranes via an endosomal intermediate is also confirmed in noradrenergic neurons. Finally, colocalization of retrieved DbetaH and retrieved p38 in stimulated neurons indicates that the two sets of constituents intermix. These data provide the first experimental evidence for a common early endosome in which SSV and LDV membrane constituents are internalized after exocytosis and imply that endosomal sorting is an important process for the generation of different secretory vesicles in the noradrenergic nerve terminal.

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Arf6 regulates the cycling and the readily releasable pool of synaptic vesicles at hippocampal synapse

eLife ◽

10.7554/elife.10116 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 24

Author(s):

Erica Tagliatti ◽

Manuela Fadda ◽

Antonio Falace ◽

Fabio Benfenati ◽

Anna Fassio

Keyword(s):

Plasma Membrane ◽

Synaptic Vesicles ◽

Small Gtpase ◽

Endosomal Sorting ◽

Releasable Pool ◽

Readily Releasable Pool ◽

Early Endosomes ◽

Hippocampal Synapses ◽

Activity Dependent ◽

Adp Ribosylation Factor

Recycling of synaptic vesicles (SVs) is a fundamental step in the process of neurotransmission. Endocytosed SV can travel directly into the recycling pool or recycle through endosomes but little is known about the molecular actors regulating the switch between these SV recycling routes. ADP ribosylation factor 6 (Arf6) is a small GTPase known to participate in constitutive trafficking between plasma membrane and early endosomes. Here, we have morphologically and functionally investigated Arf6-silenced hippocampal synapses and found an activity dependent accumulation of synaptic endosome-like organelles and increased release-competent docked SVs. These features were phenocopied by pharmacological blockage of Arf6 activation. The data reveal an unexpected role for this small GTPase in reducing the size of the readily releasable pool of SVs and in channeling retrieved SVs toward direct recycling rather than endosomal sorting. We propose that Arf6 acts at the presynapse to define the fate of an endocytosed SV.

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Faculty Opinions recommendation of Small-molecule regulation of zebrafish gene expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1066105.519078 ◽

2007 ◽

Author(s):

Brant Weinstein

Keyword(s):

Gene Expression ◽

Small Molecule

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Faculty Opinions recommendation of Small molecule control of virulence gene expression in Francisella tularensis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1168406.630587 ◽

2009 ◽

Author(s):

Vincenzo Scarlato

Keyword(s):

Gene Expression ◽

Francisella Tularensis ◽

Small Molecule ◽

Virulence Gene ◽

Virulence Gene Expression

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Faculty Opinions recommendation of Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717988167.793477443 ◽

2013 ◽

Author(s):

Patrick McNutt ◽

Ian Gut

Keyword(s):

Neuromuscular Junction ◽

Synaptic Vesicles ◽

Botulinum Neurotoxin ◽

Type A ◽

Botulinum Neurotoxin Type A

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Downregulation of Breast Cancer Gene Expression by Small Molecule Drugs

10.21236/ada427817 ◽

2004 ◽

Author(s):

Y. V. Gopal

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Small Molecule ◽

Cancer Gene ◽

Small Molecule Drugs ◽

Breast Cancer Gene

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RNA–Binding Protein HuD as a Versatile Factor in Neuronal and Non–Neuronal Systems

Biology ◽

10.3390/biology10050361 ◽

2021 ◽

Vol 10 (5) ◽

pp. 361

Author(s):

Myeongwoo Jung ◽

Eun-Kyung Lee

Keyword(s):

Gene Expression ◽

Neural Plasticity ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Novel Treatments ◽

Target Mrnas ◽

Neuronal Systems

HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. Numerous studies have shown that HuD plays essential roles in neuronal development, differentiation, neurogenesis, dendritic maturation, neural plasticity, and synaptic transmission by regulating the metabolism of target mRNAs. However, growing evidence suggests that HuD also functions as a pivotal regulator of gene expression in non–neuronal systems and its malfunction is implicated in disease pathogenesis. Comprehensive knowledge of HuD expression, abundance, molecular targets, and regulatory mechanisms will broaden our understanding of its role as a versatile regulator of gene expression, thus enabling novel treatments for diseases with aberrant HuD expression. This review focuses on recent advances investigating the emerging role of HuD, its molecular mechanisms of target gene regulation, and its disease relevance in both neuronal and non–neuronal systems.

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Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

Nature Communications ◽

10.1038/s41467-020-18789-8 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Matthieu Dos Santos ◽

Stéphanie Backer ◽

Benjamin Saintpierre ◽

Brigitte Izac ◽

Muriel Andrieu ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Transcription Factors ◽

Neuromuscular Junction ◽

Heavy Chain ◽

Transcriptional Activity ◽

Rna Seq ◽

Hybrid Fibers ◽

Adult Mice ◽

Single Nucleus

Abstract Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.

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