scholarly journals Spontaneous single synapse activity predicts evoked neurotransmission by using overlapping machinery

2020 ◽  
Author(s):  
Andreas T. Grasskamp ◽  
Meida Jusyte ◽  
Anthony W. McCarthy ◽  
Torsten W.B. Götz ◽  
Alexander M. Walter
Keyword(s):  
Neural Development ◽  
Neuromuscular Junctions ◽  
Small Subset ◽  
Postsynaptic Receptors ◽  
Voltage Gated Calcium Channels ◽  
Transmission Modes ◽  
Blocking Voltage ◽  
Molecular Machinery ◽  
Highly Correlated ◽  
And Function

AbstractSynaptic transmission relies on presynaptic neurotransmitter (NT) release from synaptic vesicles (SVs), and on NT detection by postsynaptic receptors. Two principal modes exist: action-potential (AP) evoked and AP-independent “spontaneous” transmission. Though universal to all synapses and essential for neural development and function, regulation of spontaneous transmission remains enigmatic. Mechanisms divergent from AP-evoked transmission were described, but are difficult to reconcile with its established function in adjusting AP-evoked transmission. By studying neurotransmission at individual synapses of Drosophila larval neuromuscular junctions (NMJs), we show a clear interdependence of transmission modes: Components of the AP-evoked NT-release machinery (Unc13, Syntaxin-1 and BRP) also predicted spontaneous transmission. Both modes were reduced when blocking voltage-gated calcium channels and engaged an overlapping pool of SVs and NT-receptors. While a small subset (~21%) of spontaneously active synapses appeared limited to this mode, most also mediated AP-evoked transmission and activity was highly correlated. Thus, by engaging overlapping molecular machinery, spontaneous transmission predicts AP-evoked transmission at single synapses.

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

scholarly journals Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Peng Chen ◽  
Hongyang Jing ◽  
Mingtao Xiong ◽  
Qian Zhang ◽  
Dong Lin ◽  
...  
Keyword(s):  
Neural Development ◽  
Protein Level ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Pathophysiological Mechanism ◽  
Brain Disorders ◽  
Spine Density ◽  
Genes Encoding ◽  
High Level ◽  
And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

scholarly journals Cell-specific expression and individual function of prohormone convertase PC1/3 in Tribolium larval growth highlights major evolutionary changes between beetle and fly neuroendocrine systems

EvoDevo ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sonja Fritzsche ◽  
Vera S. Hunnekuhl
Keyword(s):  
Larval Growth ◽  
Neuroendocrine System ◽  
Small Subset ◽  
Specific Cell ◽  
Specific Expression ◽  
Individual Function ◽  
Evolutionary Changes ◽  
Cell Groups ◽  
Cell Type Specific Expression ◽  
And Function

Abstract Background The insect neuroendocrine system acts in the regulation of physiology, development and growth. Molecular evolution of this system hence has the potential to allow for major biological differences between insect groups. Two prohormone convertases, PC1/3 and PC2, are found in animals and both function in the processing of neuropeptide precursors in the vertebrate neurosecretory pathway. Whereas PC2-function is conserved between the fly Drosophila and vertebrates, ancestral PC1/3 was lost in the fly lineage and has not been functionally studied in any protostome. Results In order to understand its original functions and the changes accompanying the gene loss in the fly, we investigated PC1/3 and PC2 expression and function in the beetle Tribolium castaneum. We found that PC2 is broadly expressed in the nervous system, whereas surprisingly, PC1/3 expression is restricted to specific cell groups in the posterior brain and suboesophageal ganglion. Both proteases have parallel but non-redundant functions in adult beetles’ viability and fertility. Female infertility following RNAi is caused by a failure to deposit sufficient yolk to the developing oocytes. Larval RNAi against PC2 produced moulting defects where the larvae were not able to shed their old cuticle. This ecdysis phenotype was also observed in a small subset of PC1/3 knockdown larvae and was strongest in a double knockdown. Unexpectedly, most PC1/3-RNAi larvae showed strongly reduced growth, but went through larval moults despite minimal to zero weight gain. Conclusions The cell type-specific expression of PC1/3 and its essential requirement for larval growth highlight the important role of this gene within the insect neuroendocrine system. Genomic conservation in most insect groups suggests that it has a comparable individual function in other insects as well, which has been replaced by alternative mechanisms in flies.

scholarly journals Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

Membranes ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 796
Author(s):  
Yi-An Chen ◽  
Cheng-Hsiu Lu ◽  
Chien-Chih Ke ◽  
Ren-Shyan Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Synaptic Loss ◽  
Molecular Machinery ◽  
And Function ◽  
Preclinical And Clinical Studies ◽  
Ad Therapy

Alzheimer’s disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field.

scholarly journals Progressive methylation of POU5F1 regulatory regions during blastocyst development

Reproduction ◽  
2018 ◽  
Vol 156 (2) ◽  
pp. 145-161 ◽  
Author(s):  
E Canon ◽  
L Jouneau ◽  
T Blachère ◽  
N Peynot ◽  
N Daniel ◽  
...  
Keyword(s):  
De Novo ◽  
Regulatory Region ◽  
Upstream Region ◽  
Distal Enhancer ◽  
Blastocyst Development ◽  
Differentiated Cells ◽  
Rabbit Blastocyst ◽  
Highly Correlated ◽  
And Function

ThePOU5F1gene encodes one of the ‘core’ transcription factors necessary to establish and maintain pluripotency in mammals. Its function depends on its precise level of expression, so its transcription has to be tightly regulated. To date, few conserved functional elements have been identified in its 5′ regulatory region: a distal and a proximal enhancer, and a minimal promoter, epigenetic modifications of which interfere withPOU5F1expression and function inin vitro-derived cell lines. Also, its permanent inactivation in differentiated cells depends onde novomethylation of its promoter. However, little is known about the epigenetic regulation ofPOU5F1expression in the embryo itself. We used the rabbit blastocyst as a model to analyze the methylation dynamics of thePOU5F15′ upstream region, relative to its regulated expression in different compartments of the blastocyst over a 2-day period of development. We evidenced progressive methylation of the 5′ regulatory region and the first exon accompanying differentiation and the gradual repression ofPOU5F1. Methylation started in the early trophectoderm before complete transcriptional inactivation. Interestingly, the distal enhancer, which is known to be active in naïve pluripotent cells only, retained a very low level of methylation in primed pluripotent epiblasts and remained less methylated in differentiated compartments than the proximal enhancer. This detailed study identified CpGs with the greatest variations in methylation, as well as groups of CpGs showing a highly correlated behavior, during differentiation. Moreover, our findings evidenced few CpGs with very specific behavior during this period of development.

scholarly journals Regulation of murine copper homeostasis by members of the COMMD protein family

2020 ◽  
Vol 14 (1) ◽  
pp. dmm045963
Author(s):  
Amika Singla ◽  
Qing Chen ◽  
Kohei Suzuki ◽  
Jie Song ◽  
Alina Fedoseienko ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Copper Accumulation ◽  
Copper Transporter ◽  
Copper Excretion ◽  
Copper Absorption ◽  
Hepatic Copper ◽  
High Copper ◽  
Molecular Machinery ◽  
And Function

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

scholarly journals Genetic Analysis of Collagen Q: Roles in Acetylcholinesterase and Butyrylcholinesterase Assembly and in Synaptic Structure and Function

1999 ◽  
Vol 144 (6) ◽  
pp. 1349-1360 ◽  
Author(s):  
Guoping Feng ◽  
Eric Krejci ◽  
Jordi Molgo ◽  
Jeanette M. Cunningham ◽  
Jean Massoulié ◽  
...  
Keyword(s):  
Neuromuscular Junctions ◽  
Synaptic Cleft ◽  
Neuromuscular Function ◽  
Nerve Terminals ◽  
Compensatory Mechanisms ◽  
Structural Mechanism ◽  
Synaptic Structure ◽  
Cardiac Muscles ◽  
And Function ◽  
Early Phases

Acetylcholinesterase (AChE) occurs in both asymmetric forms, covalently associated with a collagenous subunit called Q (ColQ), and globular forms that may be either soluble or membrane associated. At the skeletal neuromuscular junction, asymmetric AChE is anchored to the basal lamina of the synaptic cleft, where it hydrolyzes acetylcholine to terminate synaptic transmission. AChE has also been hypothesized to play developmental roles in the nervous system, and ColQ is also expressed in some AChE-poor tissues. To seek roles of ColQ and AChE at synapses and elsewhere, we generated ColQ-deficient mutant mice. ColQ−/− mice completely lacked asymmetric AChE in skeletal and cardiac muscles and brain; they also lacked asymmetric forms of the AChE homologue, butyrylcholinesterase. Thus, products of the ColQ gene are required for assembly of all detectable asymmetric AChE and butyrylcholinesterase. Surprisingly, globular AChE tetramers were also absent from neonatal ColQ−/− muscles, suggesting a role for the ColQ gene in assembly or stabilization of AChE forms that do not themselves contain a collagenous subunit. Histochemical, immunohistochemical, toxicological, and electrophysiological assays all indicated absence of AChE at ColQ−/− neuromuscular junctions. Nonetheless, neuromuscular function was initially robust, demonstrating that AChE and ColQ do not play obligatory roles in early phases of synaptogenesis. Moreover, because acute inhibition of synaptic AChE is fatal to normal animals, there must be compensatory mechanisms in the mutant that allow the synapse to function in the chronic absence of AChE. One structural mechanism appears to be a partial ensheathment of nerve terminals by Schwann cells. Compensation was incomplete, however, as animals lacking ColQ and synaptic AChE failed to thrive and most died before they reached maturity.

STRUCTURE AND FUNCTION OF NEUROMUSCULAR JUNCTIONS IN THE VASTUS LATERALIS OF MAN

Brain ◽  
1992 ◽  
Vol 115 (2) ◽  
pp. 451-478 ◽  
Author(s):  
E. BOLLEN ◽  
J. C. DEN HEYER ◽  
M. H. J. TOLSMA ◽  
S. BELLAR ◽  
J. E. BOS ◽  
...  
Keyword(s):  
Neuromuscular Junctions ◽  
Vastus Lateralis ◽  
Structure And Function ◽  
And Function

scholarly journals MicroRNAs Regulate Multiple Aspects of Locomotor Behavior in Drosophila

2019 ◽  
Vol 10 (1) ◽  
pp. 43-55
Author(s):  
Nathan C. Donelson ◽  
Richa Dixit ◽  
Israel Pichardo-Casas ◽  
Eva Y. Chiu ◽  
Robert T. Ohman ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Development ◽  
Locomotor Behavior ◽  
Temperature Dependent ◽  
Motor Circuits ◽  
The Many ◽  
And Function ◽  
Post Transcriptional Regulation ◽  
Movement Tracking

Locomotion is an ancient and fundamental output of the nervous system required for animals to perform many other complex behaviors. Although the formation of motor circuits is known to be under developmental control of transcriptional mechanisms that define the fates and connectivity of the many neurons, glia and muscle constituents of these circuits, relatively little is known about the role of post-transcriptional regulation of locomotor behavior. MicroRNAs have emerged as a potentially rich source of modulators for neural development and function. In order to define the microRNAs required for normal locomotion in Drosophila melanogaster, we utilized a set of transgenic Gal4-dependent competitive inhibitors (microRNA sponges, or miR-SPs) to functionally assess ca. 140 high-confidence Drosophila microRNAs using automated quantitative movement tracking systems followed by multiparametric analysis. Using ubiquitous expression of miR-SP constructs, we identified a large number of microRNAs that modulate aspects of normal baseline adult locomotion. Addition of temperature-dependent Gal80 to identify microRNAs that act during adulthood revealed that the majority of these microRNAs play developmental roles. Comparison of ubiquitous and neural-specific miR-SP expression suggests that most of these microRNAs function within the nervous system. Parallel analyses of spontaneous locomotion in adults and in larvae also reveal that very few of the microRNAs required in the adult overlap with those that control the behavior of larval motor circuits. These screens suggest that a rich regulatory landscape underlies the formation and function of motor circuits and that many of these mechanisms are stage and/or parameter-specific.

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