scholarly journals The Nucleolar δ Isoform of Adapter Protein SH2B1 Enhances Morphological Complexity and Function of Cultured Neurons

2022 ◽  
Author(s):  
Jessica L. Cote ◽  
Paul B. Vander ◽  
Michael Ellis ◽  
Joel M. Cline ◽  
Nadezhda Svezhova ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Hippocampal Neurons ◽  
Adapter Protein ◽  
Neurotrophin Receptors ◽  
Neurite Length ◽  
Human Obesity ◽  
Induced Expression ◽  
Alternatively Spliced ◽  
And Function ◽  
The Brain

The adapter protein SH2B1 is recruited to neurotrophin receptors including TrkB, receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that the four alternatively spliced isoforms of SH2B1 are important determinants of neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1−/- (KO) mice exhibit decreased neurite complexity and length and BDNF-induced expression of synapse-related immediate early genes Egr1 and Arc. Reintroduction of each SH2B1 isoform into KO neurons increases neurite complexity; the brain-specific δ isoform also increases total neurite length. Human obesity-associated variants, when expressed in SH2B1δ, alter neurite complexity, suggesting that a decrease or increase in neurite branching may have deleterious effects that contribute to the severe childhood obesity and neurobehavioral abnormalities associated with these variants. Surprisingly, in contrast to SH2B1α, β, and γ, which localize primarily in the cytoplasm and plasma membrane, SH2B1δ localizes primarily in nucleoli. Some SH2B1δ is also present in the plasma membrane and nucleus. Nucleolar localization, driven by two highly basic regions unique to SH2B1δ, is required for SH2B1δ to maximally increase neurite complexity and BDNF-induced expression of Egr1, Arc, and FosL1.

scholarly journals Deletion of the Brain-Specific α and δ Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity

2020 ◽  
Author(s):  
Jessica L. Cote ◽  
Lawrence S. Argetsinger ◽  
Anabel Flores ◽  
Alan C. Rupp ◽  
Joel M. Cline ◽  
...  
Keyword(s):  
Energy Balance ◽  
Adapter Protein ◽  
Wild Type ◽  
Leptin Sensitivity ◽  
High Fat Diets ◽  
Independent Mechanism ◽  
Alternatively Spliced ◽  
Fat Diets ◽  
The Brain ◽  
Inactivating Mutations

Mice lacking SH2B1 and humans with inactivating mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively-spliced SH2B1<i> </i>isoforms<i>,</i> SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO mice exhibit decreased food intake, protection from weight gain on standard and high fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively-spliced isoforms of SH2B1 perform different functions <i>in</i> <i>vivo</i>. <br>

scholarly journals Deletion of the brain-specific α and δ isoforms of adapter protein SH2B1 protects mice from obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Jessica L. Cote ◽  
Lawrence S. Argetsinger ◽  
Anabel Flores ◽  
Alan C. Rupp ◽  
...  
Keyword(s):  
Energy Balance ◽  
Adapter Protein ◽  
Wild Type ◽  
Leptin Sensitivity ◽  
High Fat Diets ◽  
Independent Mechanism ◽  
Alternatively Spliced ◽  
Fat Diets ◽  
The Brain ◽  
Inactivating Mutations

Mice lacking SH2B1 and humans with inactivating mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively-spliced SH2B1<i> </i>isoforms<i>,</i> SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO mice exhibit decreased food intake, protection from weight gain on standard and high fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively-spliced isoforms of SH2B1 perform different functions <i>in</i> <i>vivo</i>. <br>

scholarly journals Protein transport to the dendritic plasma membrane of cultured neurons is regulated by rab8p.

1993 ◽  
Vol 123 (1) ◽  
pp. 47-55 ◽  
Author(s):  
L A Huber ◽  
M J de Hoop ◽  
P Dupree ◽  
M Zerial ◽  
K Simons ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Hippocampal Neurons ◽  
Protein Transport ◽  
Semliki Forest Virus ◽  
Companion Paper ◽  
Small Gtpase ◽  
Cultured Neurons ◽  
Double Labeling ◽  
Basolateral Plasma Membrane ◽  
And Function

In the companion paper (Huber, L. A., S. W. Pimplikar, R. G. Parton, H. Virta, M. Zerial, and K. Simons. J. Cell Biol. 123:35-45) we reported that the small GTPase rab8p is involved in transport from the TGN to the basolateral plasma membrane in epithelia. In the present work we investigated the localization and function of rab8p in polarized hippocampal neurons. By immunofluorescence microscopy we found that rab8p localized preferentially in the somatodendritic domain, and was excluded from the axon. Double-labeling immunofluorescence showed that some of the rab8p co-localized in the dendrites with the Semliki Forest Virus glycoprotein E2 (SFV-E2). An antisense oligonucleotide approach was used to investigate the role of rab8p in dendritic transport of newly synthesized viral glycoproteins. Antisense oligonucleotides corresponding to the initiation region of the rab8 coding sequence were added to the cultured neurons for four days. This treatment resulted in a significant decrease in cellular levels of rab8p and transport of SFV-E2 from the cell body to the dendrites was significantly reduced. However, no effect was observed on axonal transport of influenza HA. From these results we conclude that rab8p is involved in transport of proteins to the dendritic surface in neurons.

scholarly journals A peroxisome deficiency–induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway

2020 ◽  
Vol 295 (16) ◽  
pp. 5321-5334 ◽  
Author(s):  
Yuichi Abe ◽  
Masanori Honsho ◽  
Ryoko Kawaguchi ◽  
Takashi Matsuzaki ◽  
Yayoi Ichiki ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Cell Communication ◽  
Brain Derived Neurotrophic Factor ◽  
Bdnf Expression ◽  
Multiple Organs ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

scholarly journals Neurite growth kinetics regulation through hydrostatic pressure in a novel triangle-shaped neurofluidic system

2021 ◽  
Author(s):  
B. G. C. Maisonneuve ◽  
A. Batut ◽  
C. Varela ◽  
J. Vieira ◽  
M. Gleyzes ◽  
...  
Keyword(s):  
Hydrostatic Pressure ◽  
Growth Kinetics ◽  
Hippocampal Neurons ◽  
Neurite Growth ◽  
Neurite Length ◽  
Triangular Design ◽  
Kinetics Of ◽  
The Brain

AbstractMicrofluidic neuro-engineering design rules have been widely explored to create in vitro neural networks with the objective to replicate physiologically relevant structures of the brain. Several neurofluidic strategies have been reported to study the connectivity of neurons, either within a population or between two separated populations, through the control of the directionality of their neuronal projections. Yet, the in vitro regulation of the growth kinetics of those projections remains challenging. Here, we describe a new neurofluidic chip with a triangular design that allows the accurate monitoring of neurite growth kinetics in a neuronal culture. This device permits to measure the maximum achievable length of projecting neurites over time and to report variations in neurite length under several conditions. Our results show that, by applying positive or negative hydrostatic pressure to primary rat hippocampal neurons, neurite growth kinetics can be tuned. This work presents a pioneering approach for the precise characterization of neurite length dynamics within an in vitro minimalistic environment.

Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids

2019 ◽  
Vol 30 (4) ◽  
pp. 2627-2641 ◽  
Author(s):  
Nicola Brandt ◽  
Ricardo Vierk ◽  
Lars Fester ◽  
Max Anstötz ◽  
Lepu Zhou ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Sex Chromosome ◽  
Chromosome Complement ◽  
Hippocampal Synaptic Plasticity ◽  
And Function ◽  
Mushroom Spines ◽  
The Brain

Abstract Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.

scholarly journals Deletion of the Brain-Specific α and δ Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity

2020 ◽  
Author(s):  
Jessica L. Cote ◽  
Lawrence S. Argetsinger ◽  
Anabel Flores ◽  
Alan C. Rupp ◽  
Joel M. Cline ◽  
...  
Keyword(s):  
Energy Balance ◽  
Adapter Protein ◽  
Wild Type ◽  
Leptin Sensitivity ◽  
High Fat Diets ◽  
Independent Mechanism ◽  
Alternatively Spliced ◽  
Fat Diets ◽  
The Brain ◽  
Inactivating Mutations

Mice lacking SH2B1 and humans with inactivating mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively-spliced SH2B1<i> </i>isoforms<i>,</i> SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO mice exhibit decreased food intake, protection from weight gain on standard and high fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively-spliced isoforms of SH2B1 perform different functions <i>in</i> <i>vivo</i>. <br>

Ultrastructure of developing visual cortical synapses in the cat superior colliculus

1991 ◽  
Vol 49 ◽  
pp. 156-157
Author(s):  
Caroline A. Miller ◽  
Laura L. Bruce
Keyword(s):  
Superior Colliculus ◽  
Phosphate Buffer ◽  
Receptive Fields ◽  
Visual Cortical Area ◽  
Cortical Synapses ◽  
Visual Cortical ◽  
And Function ◽  
Phosphate Buffered Saline ◽  
The Brain ◽  
Cat Superior Colliculus

The first visual cortical axons arrive in the cat superior colliculus by the time of birth. Adultlike receptive fields develop slowly over several weeks following birth. The developing cortical axons go through a sequence of changes before acquiring their adultlike morphology and function. To determine how these axons interact with neurons in the colliculus, cortico-collicular axons were labeled with biocytin (an anterograde neuronal tracer) and studied with electron microscopy.Deeply anesthetized animals received 200-500 nl injections of biocytin (Sigma; 5% in phosphate buffer) in the lateral suprasylvian visual cortical area. After a 24 hr survival time, the animals were deeply anesthetized and perfused with 0.9% phosphate buffered saline followed by fixation with a solution of 1.25% glutaraldehyde and 1.0% paraformaldehyde in 0.1M phosphate buffer. The brain was sectioned transversely on a vibratome at 50 μm. The tissue was processed immediately to visualize the biocytin.

scholarly journals PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Javier Emperador-Melero ◽  
Man Yan Wong ◽  
Shan Shan H. Wang ◽  
Giovanni de Nola ◽  
Hajnalka Nyitrai ◽  
...  
Keyword(s):  
Phase Separation ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Phosphorylation Site ◽  
Double Knockout ◽  
Zone Structure ◽  
Presynaptic Nerve Terminal ◽  
Condensate Formation ◽  
And Function

AbstractThe active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid–liquid phase separation, a mechanism for the formation of membrane-less subcellular compartments. Here, we show that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation in transfected HEK293T cells. Condensate formation is triggered by Liprin-α3 PKC-phosphorylation at serine-760, and RIM and Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies establish phosphorylation of Liprin-α3 serine-760 in transfected cells and mouse brain tissue. In primary hippocampal neurons of newly generated Liprin-α2/α3 double knockout mice, synaptic levels of RIM and Munc13 are reduced and the pool of releasable vesicles is decreased. Re-expression of Liprin-α3 restored these presynaptic defects, while mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented this rescue. Finally, PKC activation in these neurons acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. Our findings indicate that PKC-mediated phosphorylation of Liprin-α3 triggers its phase separation and modulates active zone structure and function.

Revision Targeted Muscle Reinnervation Improves Secondary Pain Insult in an Upper Extremity Amputee: A Case Report

Hand ◽  
2021 ◽  
pp. 155894472199246
Author(s):  
David D. Rivedal ◽  
Meng Guo ◽  
James Sanger ◽  
Aaron Morgan
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerves ◽  
Nerve Biopsy ◽  
Sensory Cortex ◽  
Denervated Muscle ◽  
Unique Case ◽  
Targeted Muscle Reinnervation ◽  
Muscle Reinnervation ◽  
And Function ◽  
The Brain

Targeted muscle reinnervation (TMR) has been shown to improve phantom and neuropathic pain in both the acute and chronic amputee population. Through rerouting of major peripheral nerves into a newly denervated muscle, TMR harnesses the plasticity of the brain, helping to revert the sensory cortex back toward the preinsult state, effectively reducing pain. We highlight a unique case of an above-elbow amputee for sarcoma who was initially treated with successful transhumeral TMR. Following inadvertent nerve biopsy of a TMR coaptation site, his pain returned, and he was unable to don his prosthetic. Revision of his TMR to a more proximal level was performed, providing improved pain and function of the amputated arm. This is the first report to highlight the concept of secondary neuroplasticity and successful proximal TMR revision in the setting of multiple insults to the same extremity.

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