Connexin43 controls N-cadherin transcription during collective cell migration

AbstractConnexins are the primary components of gap junctions, providing direct links between cells in many physiological processes, including cell migration and cancer metastasis. Exactly how cell migration is controlled by gap junctions remains a mystery. To shed light on this, we investigated the role of Connexin43 in collective cell migration during embryo development using the neural crest, an embryonic cell population whose migratory behavior has been likened to cancer invasion. We discovered that Connexin43 is required for contact inhibition of locomotion by directly regulating the transcription of N-cadherin. For this function, the Connexin43 carboxy tail interacts with Basic Transcription Factor 3, which mediates its translocation to the nucleus. Together, they bind to the n-cad promotor regulating n-cad transcription. Thus, we uncover an unexpected, gap junction-independent role for Connexin43 in collective migration that illustrates the possibility that connexins, in general, may be important for a wide variety of cellular processes that we are only beginning to understand.HighlightsCx43 regulates collective directional migration of neural crest cellsCx43 carboxy tail controls cell polarity via n-cad regulationCx43 carboxy tail localises at the nucleus and that depends on BTF3BTF3 and Cx43 carboxy tail directly interact to bind and regulate n-cad promoter activity

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Cadherins function during the collective cell migration of Xenopus Cranial Neural Crest cells: revisiting the role of E-cadherin

Mechanisms of Development ◽

10.1016/j.mod.2017.04.006 ◽

2017 ◽

Vol 148 ◽

pp. 79-88 ◽

Cited By ~ 10

Author(s):

Hélène Cousin

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Neural Crest Cells ◽

Collective Cell Migration ◽

Cranial Neural Crest ◽

Cranial Neural Crest Cells ◽

E Cadherin

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Stretch-induced endogenous electric fields drive neural crest directed collective cell migration in vivo

10.1101/2021.10.11.463916 ◽

2021 ◽

Author(s):

Fernando Ferreira ◽

Sofia Moreira ◽

Elias H Barriga

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Electric Fields ◽

Embryonic Cell ◽

Collective Cell Migration ◽

Convergent Extension ◽

Topological Features ◽

Stretch Activated Channels

Directed collective cell migration (dCCM) is essential for morphogenesis. Cell clusters migrate in inherently complex in vivo environments composed of chemical, electrical, mechanical as well as topological features. While these environmental factors have been shown to allow dCCM in vitro, our understanding of dCCM in vivo is mostly limited to chemical guidance. Thus, despite its wide biological relevance, the mechanisms that guide dCCM in vivo remain unclear. To address this, we study endogenous electric fields in relation to the migratory environment of the Xenopus laevis cephalic neural crest, an embryonic cell population that collectively and directionally migrates in vivo. Combining bioelectrical, biomechanical and molecular tools, we show that endogenous electric fields drive neural crest dCCM via electrotaxis in vivo. Moreover, we identify the voltage-sensitive phosphatase 1 (Vsp1) as a key component of the molecular mechanism used by neural crest cells to transduce electric fields into a directional cue. Furthermore, Vsp1 function is specifically required for electrotaxis, being dispensable for cell motility and chemotaxis. Finally, we reveal that endogenous electric fields are mechanoelectrically established. Mechanistically, convergent extension movements of the neural fold generate membrane tension, which in turn opens stretch-activated channels to mobilise the ions required to fuel electric fields. Overall, our results reveal a mechanism of cell guidance, where electrotaxis emerges from the mechanoelectrical and molecular interplay between neighbouring tissues. More broadly, our data contribute to validate the, otherwise understudied, functions of endogenous bioelectrical stimuli in morphogenetic processes.

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The mechanosensitive channel Piezo1 cooperates with Semaphorin to control neural crest migration

Development ◽

10.1242/dev.200001 ◽

2021 ◽

Author(s):

Brenda Canales Coutiño ◽

Roberto Mayor

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Embryonic Cell ◽

Extracellular Signals ◽

Rac1 Activity ◽

Cytoskeletal Dynamics ◽

Mechanosensitive Ion Channel ◽

Neural Crest Migration

Cells are permanently exposed to a multitude of different kind of signals; however how cells respond to simultaneous extracellular signals within a complex in vivo environment is poorly understood. Here, we studied the role of the mechanosensitive ion channel Piezo1 on the migration of the neural crest (NC), a multipotent embryonic cell population. We identify that Piezo1 is required for the migration of Xenopus cephalic NC. We show that loss of Piezo1 promotes focal adhesion turnover and cytoskeletal dynamics by controlling Rac1 activity, leading to increased speed of migration. Moreover, overactivation of Rac1, due to Piezo1 inhibition, counteracts cell migration inhibitory signals by Semaphorins 3A and 3F, generating aberrant neural crest invasion in vivo. Thus, we find that, for directional migration in vivo, neural crest cells require a tight regulation of Rac1, by Semaphorins and Piezo1. We reveal here that a balance between a myriad of signals through Rac1 dictates cell migration in vivo, a mechanism that is likely to be conserved in other cell migration processes.

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Fascin regulates protrusions and delamination to mediate invasive, collective cell migration in vivo

10.1101/734475 ◽

2019 ◽

Cited By ~ 1

Author(s):

Maureen C. Lamb ◽

Kelsey K. Anliker ◽

Tina L. Tootle

Keyword(s):

Cell Migration ◽

Cancer Metastasis ◽

Collective Cell Migration ◽

Nurse Cells ◽

Border Cells ◽

Border Cell ◽

Migration Data ◽

Border Cell Migration

AbstractFascin is an actin bundling protein that is essential for developmental cell migrations and promotes cancer metastasis. In addition to bundling actin, Fascin has several actin-independent roles. Border cell migration during Drosophila oogenesis provides an excellent model to study Fascin’s various roles during invasive, collective cell migration. Border cell migration requires Fascin. Fascin functions not only within the migrating border cells, but also within the nurse cells, the substrate for this migration. Loss of Fascin results in increased, shorter and mislocalized protrusions during migration. Data supports the model that Fascin promotes the activity of Enabled, an actin elongating factor, to regulate migration. Additionally, loss of Fascin inhibits border cell delamination. These defects are partially due to altered E-cadherin localization in the border cells; this is predicted to be an actin-independent role of Fascin. Overall, Fascin is essential for multiple aspects of this invasive, collective cell migration, and functions in both actin-dependent and -independent manners. These findings have implications beyond Drosophila, as border cell migration has emerged as a model to study mechanisms mediating cancer metastasis.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽

10.3390/cells8091037 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1037 ◽

Cited By ~ 6

Author(s):

Cho ◽

Kim ◽

Baek ◽

Kim ◽

Lee

Keyword(s):

Cell Migration ◽

Cancer Progression ◽

Anticancer Agents ◽

Rho Gtpases ◽

Rho Gtpase ◽

Regulatory Mechanisms ◽

Malignant Phenotype ◽

Cellular Processes ◽

Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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Neural crest migration: interplay between chemorepellents, chemoattractants, contact inhibition, epithelial-mesenchymal transition, and collective cell migration

Wiley Interdisciplinary Reviews Developmental Biology ◽

10.1002/wdev.28 ◽

2012 ◽

Vol 1 (3) ◽

pp. 435-445 ◽

Cited By ~ 62

Author(s):

Eric Theveneau ◽

Roberto Mayor

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Epithelial Mesenchymal Transition ◽

Contact Inhibition ◽

Collective Cell Migration ◽

Mesenchymal Transition ◽

Neural Crest Migration

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The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes

Frontiers in Pharmacology ◽

10.3389/fphar.2021.640441 ◽

2021 ◽

Vol 12 ◽

Author(s):

Roberta Lattanzi ◽

Cinzia Severini ◽

Daniela Maftei ◽

Luciano Saso ◽

Aldo Badiani

Keyword(s):

Pain Perception ◽

G Protein Coupled Receptors ◽

Cellular Processes ◽

Prokineticin 2 ◽

Physiological Processes ◽

Pathological Conditions ◽

Double Function ◽

The Central Nervous System ◽

G Protein Coupled

The prokineticin (PK) family, prokineticin 1 and Bv8/prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.

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Abstract P141: GYY4137, a H 2 S Donor, Normalizes miR-132 Targeted Sirt1 and Ace2 Expression to Improve Kidney Function in Hypertension

Hypertension ◽

10.1161/hyp.68.suppl_1.p141 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Gregory Weber ◽

Sathnur Pushpakumar ◽

Utpal Sen

Keyword(s):

Blood Flow ◽

Kidney Function ◽

Expression Patterns ◽

Sirtuin 1 ◽

Ang Ii ◽

Cellular Processes ◽

Physiological Processes ◽

Epigenetic Gene Silencing ◽

Increased Blood Flow

MicroRNAs regulate several physiological processes and are implicated in various pathologies, including hypertension. Previous work indicates miR-132 targets Sirtuin 1 (Sirt1), a histone deacetylase and regulator of epigenetic gene silencing in various cellular processes. Sirt1 is expressed in the kidney; however, its role in hypertensive kidney and whether it is regulated by physiological gaseous molecules, such as hydrogen sulfide (H 2 S), is not known. In this study, we sought to determine the role of miR-132 in regulating Sirt1, Ace2 and At1 in hypertensive kidney and whether H 2 S donor, GYY4137 (GYY), could reverse these effects and mitigates renal dysfunction. Wild-type mice were treated without or with Ang-II (1000 ng/Kg/Min) and GYY (133 μM) for 4 weeks. Quantitative PCR, Western blot, and immunofluorescence assays were performed. Increased expression levels of miR-132 in hypertensive mice (3.79 fold vs control) were reduced in mice receiving GYY treatment (2.43 fold vs control). Sirt1 expression was reduced (-1.15 fold) in Ang-II mice but was upregulated in GYY (1.25 fold) and Ang-II+GYY (1.9 fold) groups. A similar effect was seen with Sirt1 protein where the expression was increased in animals treated with GYY and Ang-II+GYY (1.16, 1.03 respectively) compared to Ang-II (0.47). Ace2 in Ang-II+GYY (0.45) was increased compared to Ang-II (0.17), while At1 was reduced (0.46) compared to Ang-II (0.86). Immunofluorescence showed decreased signal of Sirt1 in the glomerulus in Ang-II mice and increased At1 in the blood vessels surrounding the glomerulus, leading to constriction of renal artery, decreased blood flow, and kidney dysfunction. These effects were alleviated in mice treated with GYY. Our data suggests that upregulation of miR-132 in hypertensive kidney decreases Sirt1 and Ace2 expression, leading to increased Ang-II signaling through the At1 receptor and GYY supplementation reverses these expression patterns, leading to increased blood flow and kidney function.

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