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Article ; Online: Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

Shataakshi Dube O'Neil / Bence Rácz / Walter Evan Brown / Yudong Gao / Erik J Soderblom / Ryohei Yasuda / Scott H Soderling

eLife, Vol

2021 Volume 10

Abstract: In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a ... ...

Abstract	In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.
Keywords	short-term plasticity ; presynapse ; cytoskeleton ; proteomics ; Rac1 ; 2pFLIM ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Action potential-coupled Rho GTPase signaling drives presynaptic plasticity.

O'Neil, Shataakshi Dube / Rácz, Bence / Brown, Walter Evan / Gao, Yudong / Soderblom, Erik J / Yasuda, Ryohei / Soderling, Scott H

eLife

2021 Volume 10

Abstract	In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/metabolism ; Action Potentials/physiology ; Animals ; Calcium/metabolism ; Cytoskeleton/metabolism ; Hippocampus ; Mice ; Neuronal Plasticity/physiology ; Neuropeptides/metabolism ; Proteomics ; Synapses/physiology ; Synaptic Vesicles/metabolism ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism ; rho GTP-Binding Proteins/genetics ; rho GTP-Binding Proteins/metabolism
Chemical Substances	Actins ; Neuropeptides ; Rac1 protein, mouse ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-07-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.63756
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: In vivo proximity proteomics of nascent synapses reveals a novel regulator of cytoskeleton-mediated synaptic maturation.

Spence, Erin F / Dube, Shataakshi / Uezu, Akiyoshi / Locke, Margaret / Soderblom, Erik J / Soderling, Scott H

Nature communications

2019 Volume 10, Issue 1, Page(s) 386

Abstract: Excitatory synapse formation during development involves the complex orchestration of both structural and functional alterations at the postsynapse. However, the molecular mechanisms that underlie excitatory synaptogenesis are only partially resolved, in ...

Abstract	Excitatory synapse formation during development involves the complex orchestration of both structural and functional alterations at the postsynapse. However, the molecular mechanisms that underlie excitatory synaptogenesis are only partially resolved, in part because the internal machinery of developing synapses is largely unknown. To address this, we apply a chemicogenetic approach, in vivo biotin identification (iBioID), to discover aspects of the proteome of nascent synapses. This approach uncovered sixty proteins, including a previously uncharacterized protein, CARMIL3, which interacts in vivo with the synaptic cytoskeletal regulator proteins SrGAP3 (or WRP) and actin capping protein. Using new CRISPR-based approaches, we validate that endogenous CARMIL3 is localized to developing synapses where it facilitates the recruitment of capping protein and is required for spine structural maturation and AMPAR recruitment associated with synapse unsilencing. Together these proteomic and functional studies reveal a previously unknown mechanism important for excitatory synapse development in the developing perinatal brain.
MeSH term(s)	Actin Capping Proteins/genetics ; Actin Capping Proteins/metabolism ; Animals ; Biotin ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; Cytoskeletal Proteins/metabolism ; Cytoskeleton/metabolism ; Dendritic Spines/metabolism ; Excitatory Postsynaptic Potentials/physiology ; GTPase-Activating Proteins ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Mice, Inbred C57BL ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Microtubules/metabolism ; Neurogenesis/genetics ; Neurogenesis/physiology ; Neurons/metabolism ; Proteome/genetics ; Proteome/metabolism ; Proteomics ; Synapses/genetics ; Synapses/metabolism
Chemical Substances	Actin Capping Proteins ; CARMIL1 protein, human ; Carmil1 protein, mouse ; Cytoskeletal Proteins ; GTPase-Activating Proteins ; Microfilament Proteins ; Proteome ; Srgap3 protein, mouse ; Biotin (6SO6U10H04)
Language	English
Publishing date	2019-01-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-08288-w
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Article ; Online: In vivo proximity proteomics of nascent synapses reveals a novel regulator of cytoskeleton-mediated synaptic maturation

Erin F. Spence / Shataakshi Dube / Akiyoshi Uezu / Margaret Locke / Erik J. Soderblom / Scott H. Soderling

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 16

Abstract: The internal molecular mechanisms that underlie excitatory synaptogenesis remain poorly characterized. This study utilizes a chemogenetic approach, in vivo biotin identification (iBioID), to discover previously uncharacterized proteins at nascent ... ...

Abstract	The internal molecular mechanisms that underlie excitatory synaptogenesis remain poorly characterized. This study utilizes a chemogenetic approach, in vivo biotin identification (iBioID), to discover previously uncharacterized proteins at nascent synapses. CARMIL3 is identified as a cytoskeletal protein that facilitates spine maturation and AMPAR recruitment.
Keywords	Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In vivo proximity proteomics of nascent synapses reveals a novel regulator of cytoskeleton-mediated synaptic maturation

Erin F. Spence / Shataakshi Dube / Akiyoshi Uezu / Margaret Locke / Erik J. Soderblom / Scott H. Soderling

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 16

Abstract	The internal molecular mechanisms that underlie excitatory synaptogenesis remain poorly characterized. This study utilizes a chemogenetic approach, in vivo biotin identification (iBioID), to discover previously uncharacterized proteins at nascent synapses. CARMIL3 is identified as a cytoskeletal protein that facilitates spine maturation and AMPAR recruitment.
Keywords	Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Master Regulators and Cofactors of Human Neuronal Cell Fate Specification Identified by CRISPR Gene Activation Screens.

Black, Joshua B / McCutcheon, Sean R / Dube, Shataakshi / Barrera, Alejandro / Klann, Tyler S / Rice, Grayson A / Adkar, Shaunak S / Soderling, Scott H / Reddy, Timothy E / Gersbach, Charles A

Cell reports

2020 Volume 33, Issue 9, Page(s) 108460

Abstract: Technologies to reprogram cell-type specification have revolutionized the fields of regenerative medicine and disease modeling. Currently, the selection of fate-determining factors for cell reprogramming applications is typically a laborious and low- ... ...

Abstract	Technologies to reprogram cell-type specification have revolutionized the fields of regenerative medicine and disease modeling. Currently, the selection of fate-determining factors for cell reprogramming applications is typically a laborious and low-throughput process. Therefore, we use high-throughput pooled CRISPR activation (CRISPRa) screens to systematically map human neuronal cell fate regulators. We utilize deactivated Cas9 (dCas9)-based gene activation to target 1,496 putative transcription factors (TFs) in the human genome. Using a reporter of neuronal commitment, we profile the neurogenic activity of these factors in human pluripotent stem cells (PSCs), leading to a curated set of pro-neuronal factors. Activation of pairs of TFs reveals neuronal cofactors, including E2F7, RUNX3, and LHX8, that improve conversion efficiency, subtype specificity, and maturation of neuronal cell types. Finally, using multiplexed gene regulation with orthogonal CRISPR systems, we demonstrate improved neuronal differentiation with concurrent activation and repression of target genes, underscoring the power of CRISPR-based gene regulation for programming complex cellular phenotypes.
MeSH term(s)	CRISPR-Cas Systems/genetics ; Cell Differentiation ; Gene Expression Regulation/genetics ; Humans ; Neurons/metabolism ; Transcriptional Activation/genetics
Language	English
Publishing date	2020-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108460
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Article ; Online: Master Regulators and Cofactors of Human Neuronal Cell Fate Specification Identified by CRISPR Gene Activation Screens

Joshua B. Black / Sean R. McCutcheon / Shataakshi Dube / Alejandro Barrera / Tyler S. Klann / Grayson A. Rice / Shaunak S. Adkar / Scott H. Soderling / Timothy E. Reddy / Charles A. Gersbach

Cell Reports, Vol 33, Iss 9, Pp 108460- (2020)

2020

Abstract: Summary: Technologies to reprogram cell-type specification have revolutionized the fields of regenerative medicine and disease modeling. Currently, the selection of fate-determining factors for cell reprogramming applications is typically a laborious and ...

Abstract	Summary: Technologies to reprogram cell-type specification have revolutionized the fields of regenerative medicine and disease modeling. Currently, the selection of fate-determining factors for cell reprogramming applications is typically a laborious and low-throughput process. Therefore, we use high-throughput pooled CRISPR activation (CRISPRa) screens to systematically map human neuronal cell fate regulators. We utilize deactivated Cas9 (dCas9)-based gene activation to target 1,496 putative transcription factors (TFs) in the human genome. Using a reporter of neuronal commitment, we profile the neurogenic activity of these factors in human pluripotent stem cells (PSCs), leading to a curated set of pro-neuronal factors. Activation of pairs of TFs reveals neuronal cofactors, including E2F7, RUNX3, and LHX8, that improve conversion efficiency, subtype specificity, and maturation of neuronal cell types. Finally, using multiplexed gene regulation with orthogonal CRISPR systems, we demonstrate improved neuronal differentiation with concurrent activation and repression of target genes, underscoring the power of CRISPR-based gene regulation for programming complex cellular phenotypes.
Keywords	transcription factor ; CRISPR ; CRISPR activation ; neuronal differentiation ; CRISPR screening ; gene regulation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Vivo Delivery and Activation of Masked Fluorogenic Hydrolase Substrates by Endogenous Hydrolases in C. elegans.

Dube, Shataakshi / Dube, Hitesh / Green, Nicole B / Larsen, Erik M / White, Alex / Johnson, R Jeremy / Kowalski, Jennifer R

Chembiochem : a European journal of chemical biology

2017 Volume 18, Issue 18, Page(s) 1807–1813

Abstract: Protein expression and localization are often studied in vivo by tagging molecules with green fluorescent protein (GFP), yet subtle changes in protein levels are not easily detected. To develop a sensitive in vivo method to amplify fluorescence signals ... ...

Abstract	Protein expression and localization are often studied in vivo by tagging molecules with green fluorescent protein (GFP), yet subtle changes in protein levels are not easily detected. To develop a sensitive in vivo method to amplify fluorescence signals and allow cell-specific quantification of protein abundance changes, we sought to apply an enzyme-activated cellular fluorescence system in vivo by delivering ester-masked fluorophores to Caenorhabditis elegans neurons expressing porcine liver esterase (PLE). To aid uptake into sensory neuron membranes, we synthesized two novel fluorogenic hydrolase substrates with long hydrocarbon tails. Recombinant PLE activated these fluorophores in vitro. In vivo activation occurred in sensory neurons, along with potent activation in intestinal lysosomes quantifiable by imaging and microplate and partially attributable to gut esterase 1 (GES-1) activity. These data demonstrate the promise of biorthogonal hydrolases and their fluorogenic substrates as in vivo neuronal imaging tools and for characterizing endogenous C. elegans hydrolase substrate specificities.
MeSH term(s)	Animals ; Caenorhabditis elegans/metabolism ; Contrast Media/chemistry ; Contrast Media/metabolism ; Esterases/genetics ; Esterases/metabolism ; Fluorescent Dyes/chemistry ; Fluorescent Dyes/metabolism ; Microscopy, Fluorescence ; Neurons/metabolism ; RNA, Messenger/metabolism ; Substrate Specificity ; Swine
Chemical Substances	Contrast Media ; Fluorescent Dyes ; RNA, Messenger ; Esterases (EC 3.1.-)
Language	English
Publishing date	2017-08-07
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.201700278
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Article ; Online: Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury.

Dube, Shataakshi / Matam, Tejasvi / Yen, Jessica / Mang, Henry E / Dagher, Pierre C / Hato, Takashi / Sutton, Timothy A

Journal of immunology research

2017 Volume 2017, Page(s) 4609502

Abstract: STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute ... ...

Abstract	STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of
MeSH term(s)	Acute Kidney Injury/immunology ; Animals ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/physiology ; Interleukins/metabolism ; Kidney/diagnostic imaging ; Kidney/pathology ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Renal Artery/surgery ; Reperfusion Injury/immunology ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Interleukin-22
Chemical Substances	Interleukins ; STAT3 Transcription Factor
Language	English
Publishing date	2017-10-17
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-7156
ISSN (online)	2314-7156
ISSN	2314-7156
DOI	10.1155/2017/4609502
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Article ; Online: The macrophage mediates the renoprotective effects of endotoxin preconditioning.

Hato, Takashi / Winfree, Seth / Kalakeche, Rabih / Dube, Shataakshi / Kumar, Rakesh / Yoshimoto, Momoko / Plotkin, Zoya / Dagher, Pierre C

Journal of the American Society of Nephrology : JASN

2015 Volume 26, Issue 6, Page(s) 1347–1362

Abstract: Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and ... ...

Abstract	Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.
MeSH term(s)	Acute Kidney Injury/metabolism ; Acute Kidney Injury/pathology ; Analysis of Variance ; Animals ; Blotting, Western ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Cytokines/metabolism ; Disease Models, Animal ; Endotoxins/metabolism ; Endotoxins/pharmacology ; Ischemic Preconditioning/methods ; Kidney Tubules, Proximal/cytology ; Kidney Tubules, Proximal/metabolism ; Lipopolysaccharide Receptors/metabolism ; Male ; Mice ; Oxidative Stress/physiology ; Random Allocation ; Reactive Oxygen Species/metabolism ; Sepsis/metabolism ; Sepsis/pathology ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism
Chemical Substances	Cytokines ; Endotoxins ; Lipopolysaccharide Receptors ; Reactive Oxygen Species ; Tlr4 protein, mouse ; Toll-Like Receptor 4
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2014060561
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