scholarly journals Nodal signaling regulates endodermal cell motility and actin dynamics via Rac1 and Prex1

2012 ◽  
Vol 198 (5) ◽  
pp. 941-952 ◽  
Author(s):  
Stephanie Woo ◽  
Michael P. Housley ◽  
Orion D. Weiner ◽  
Didier Y.R. Stainier
Keyword(s):  
Cell Fate ◽  
Actin Dynamics ◽  
Migration Behavior ◽  
Nodal Signaling ◽  
Nucleotide Exchange ◽  
Random Motility ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
And Migration ◽  
Endodermal Cells

Embryo morphogenesis is driven by dynamic cell behaviors, including migration, that are coordinated with fate specification and differentiation, but how such coordination is achieved remains poorly understood. During zebrafish gastrulation, endodermal cells sequentially exhibit first random, nonpersistent migration followed by oriented, persistent migration and finally collective migration. Using a novel transgenic line that labels the endodermal actin cytoskeleton, we found that these stage-dependent changes in migratory behavior correlated with changes in actin dynamics. The dynamic actin and random motility exhibited during early gastrulation were dependent on both Nodal and Rac1 signaling. We further identified the Rac-specific guanine nucleotide exchange factor Prex1 as a Nodal target and showed that it mediated Nodal-dependent random motility. Reducing Rac1 activity in endodermal cells caused them to bypass the random migration phase and aberrantly contribute to mesodermal tissues. Together, our results reveal a novel role for Nodal signaling in regulating actin dynamics and migration behavior, which are crucial for endodermal morphogenesis and cell fate decisions.

scholarly journals Modulation of Muscle Regeneration, Myogenesis, and Adipogenesis by the Rho Family Guanine Nucleotide Exchange Factor GEFT

2005 ◽  
Vol 25 (24) ◽  
pp. 11089-11101 ◽  
Author(s):  
Brad A. Bryan ◽  
Dianne C. Mitchell ◽  
Lei Zhao ◽  
Wenbin Ma ◽  
Lewis J. Stafford ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Muscle Regeneration ◽  
Mesenchymal Cell ◽  
Skeletal Muscle Regeneration ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cell Fate Decisions ◽  
Guanine Nucleotide Exchange ◽  
Rho Family

ABSTRACT Rho family guanine nucleotide exchange factors (GEFs) regulate diverse cellular processes including cytoskeletal reorganization, cell adhesion, and differentiation via activation of the Rho GTPases. However, no studies have yet implicated Rho-GEFs as molecular regulators of the mesenchymal cell fate decisions which occur during development and repair of tissue damage. In this study, we demonstrate that the steady-state protein level of the Rho-specific GEF GEFT is modulated during skeletal muscle regeneration and that gene transfer of GEFT into cardiotoxin-injured mouse tibialis anterior muscle exerts a powerful promotion of skeletal muscle regeneration in vivo. In order to molecularly characterize this regenerative effect, we extrapolate the mechanism of action by examining the consequence of GEFT expression in multipotent cell lines capable of differentiating into a number of cell types, including muscle and adipocyte lineages. Our data demonstrate that endogenous GEFT is transcriptionally upregulated during myogenic differentiation and downregulated during adipogenic differentiation. Exogenous expression of GEFT promotes myogenesis of C2C12 cells via activation of RhoA, Rac1, and Cdc42 and their downstream effector proteins, while a dominant-negative mutant of GEFT inhibits this process. Moreover, we show that GEFT inhibits insulin-induced adipogenesis in 3T3L1 preadipocytes. In summary, we provide the first evidence that the Rho family signaling pathways act as potential regulators of skeletal muscle regeneration and provide the first reported molecular mechanism illustrating how a mammalian Rho family GEF controls this process by modulating mesenchymal cell fate decisions.

scholarly journals Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

2019 ◽  
Author(s):  
Timothy J. Aikin ◽  
Amy F. Peterson ◽  
Michael J. Pokrass ◽  
Helen R. Clark ◽  
Sergi Regot
Keyword(s):  
Cell Fate ◽  
Temporal Patterns ◽  
Mapk Signaling ◽  
Paracrine Signaling ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
Epithelial Tissues ◽  
Mapk Activity ◽  
Signaling Axis ◽  
Quality Control Mechanism

ABSTRACTEpithelial tissues are constantly challenged by individual cell fate decisions while maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their signaling states and cellular behaviors creating competitive interactions that are poorly understood. Here we show that the temporal patterns of MAPK activity are decoded by the ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity coordinates both single and collective cell behaviors to maintain tissue homeostasis.

scholarly journals Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development

2018 ◽  
Author(s):  
Anna D. Senft ◽  
Elizabeth K. Bikoff ◽  
Elizabeth J. Robertson ◽  
Ita Costello
Keyword(s):  
Germ Cell ◽  
Cell Fate ◽  
Primordial Germ Cell ◽  
Genetic Dissection ◽  
Mouse Development ◽  
Cell Fate Decisions ◽  
Conditional Deletion ◽  
Bmp Signalling ◽  
And Migration ◽  
Early Mouse

AbstractThe essential roles played by Nodal and Bmp signalling during early mouse development have been extensively documented. Here we used conditional deletion strategies to investigate functional contributions made by Nodal, Bmp and Smad downstream effectors during primordial germ cell (PGC) development. We demonstrate that Nodal and its target gene Eomes provide early instructions during formation of the PGC lineage. We discovered that Smad2 inactivation in the visceral endoderm results in increased numbers of PGCs due to an expansion of the PGC niche. Smad1 is required for specification, whereas in contrast Smad4 controls the maintenance and migration of PGCs. Importantly we found that beside Blimp1, down-regulated phosphoSmad159 levels also distinguishes PGCs from their somatic neighbours so that emerging PGCs become refractory to Bmp signalling that otherwise promotes mesodermal development in the posterior epiblast. Thus balanced Nodal/Bmp signalling cues regulate germ cell versus somatic cell fate decisions in the early posterior epiblast.

scholarly journals Vav Regulates Activation of Rac but Not Cdc42 during FcγR-mediated Phagocytosis

2002 ◽  
Vol 13 (4) ◽  
pp. 1215-1226 ◽  
Author(s):  
Jayesh C. Patel ◽  
Alan Hall ◽  
Emmanuelle Caron
Keyword(s):  
Bound State ◽  
Small Gtpases ◽  
Membrane Receptors ◽  
Actin Dynamics ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Extracellular Signals ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
And Migration

Phagocytosis is the process whereby cells direct the spatially localized, receptor-driven engulfment of particulate materials. It proceeds via remodeling of the actin cytoskeleton and shares many of the core cytoskeletal components involved in adhesion and migration. Small GTPases of the Rho family have been widely implicated in coordinating actin dynamics in response to extracellular signals and during diverse cellular processes, including phagocytosis, yet the mechanisms controlling their recruitment and activation are not known. We show herein that in response to ligation of Fc receptors for IgG (FcγR), the guanine nucleotide exchange factor Vav translocates to nascent phagosomes and catalyzes GTP loading on Rac, but not Cdc42. The Vav-induced Rac activation proceeds independently of Cdc42 function, suggesting distinct roles for each GTPase during engulfment. Moreover, inhibition of Vav exchange activity or of Cdc42 activity does not prevent Rac recruitment to sites of particle attachment. We conclude that Rac is recruited to Fcγ membrane receptors in its inactive, GDP-bound state and that Vav regulates phagocytosis through subsequent catalysis of GDP/GTP exchange on Rac.

scholarly journals Kindlin-2 Modulates the Survival, Differentiation, and Migration of Induced Pluripotent Cell-Derived Mesenchymal Stromal Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Mohsen Moslem ◽  
Reto Eggenschwiler ◽  
Christian Wichmann ◽  
Raymund Buhmann ◽  
Tobias Cantz ◽  
...  
Keyword(s):  
Cell Fate ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Interleukin 2 ◽  
Pluripotent Cell ◽  
Scratch Assay ◽  
Cell Fate Decisions ◽  
Migration Potential ◽  
And Migration ◽  
Induced Pluripotent

Kindlin-2 is a multidomain intracellular protein that can be recruited to β-integrin domains to activate signaling, initiate transcriptional programs, and bind to E-cadherin. To explore its involvement in cell fate decisions in mesenchymal cells, we studied the effects of Kindlin-2 modification (overexpression/knockdown) in induced pluripotent cell-derived mesenchymal stromal cells (iPSC-MSCs). Kindlin-2 overexpression resulted in increased proliferation and reduced apoptosis of iPSC-MSCs, as well as inhibition of their differentiation towards osteocytes, adipocytes, and chondrocytes. In contrast, siRNA-mediated Kindlin-2 knockdown induced increased apoptosis and increased differentiation response in iPSC-MSCs. The ability of iPSC-MSCs to adhere to VCAM-1/SDF-1α under shear stress and to migrate in a wound scratch assay was significantly increased after Kindlin-2 overexpression. In contrast, inhibition of mixed lymphocyte reaction (MLR) was generally independent of Kindlin-2 modulation in iPSC-MSCs, except for decreased production of interleukin-2 (IL-2) after Kindlin-2 overexpression in iPS-MSCs. Thus, Kindlin-2 upregulates survival, proliferation, stemness, and migration potential in iPSC-MSCs and may therefore be beneficial in optimizing performance of iPSC-MSC in therapies.

scholarly journals Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark

2015 ◽  
Vol 29 (7) ◽  
pp. 702-717 ◽  
Author(s):  
Alessandro Bertero ◽  
Pedro Madrigal ◽  
Antonella Galli ◽  
Nina C. Hubner ◽  
Inmaculada Moreno ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cell Fate ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Nodal Signaling ◽  
Stem Cell Fate ◽  
Chromatin Mark ◽  
Cell Fate Decisions

scholarly journals Rapid changes in morphogen concentration control self-organized patterning in human embryonic stem cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Idse Heemskerk ◽  
Kari Burt ◽  
Matthew Miller ◽  
Sapna Chhabra ◽  
M Cecilia Guerra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Nodal Signaling ◽  
Cell Fate Decisions ◽  
Self Organized ◽  
Rapid Changes

During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation. We show that BMP4 response is concentration dependent, but that expression of many Nodal targets depends on rate of concentration change. Moreover, in a self-organized stem cell model for human gastrulation, expression of these genes follows rapid changes in endogenous Nodal signaling. Our study shows a striking contrast between the specific ways ligand dynamics are interpreted by two closely related signaling pathways, highlighting both the subtlety and importance of morphogen dynamics for understanding mammalian embryogenesis and designing optimized protocols for directed stem cell differentiation.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see <xref ref-type="decision-letter" rid="SA1">decision letter</xref>).

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