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Roberto Mayor - One of the best experts on this subject based on the ideXlab platform.
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redistribution of adhesive forces through src fak drives Contact Inhibition of locomotion in neural crest
Developmental Cell, 2018Co-Authors: Alice Roycroft, Andras Szabo, Isabel Bahm, Liam Daly, Guillaume Charras, Maddy Parsons, Roberto MayorAbstract:Contact Inhibition of locomotion is defined as the behavior of cells to cease migrating in their former direction after colliding with another cell. It has been implicated in multiple developmental processes and its absence has been linked to cancer invasion. Cellular forces are thought to govern this process; however, the exact role of traction through cell-matrix adhesions and tension through cell-cell adhesions during Contact Inhibition of locomotion remains unknown. Here we use neural crest cells to address this and show that cell-matrix adhesions are rapidly disassembled at the Contact between two cells upon collision. This disassembly is dependent upon the formation of N-cadherin-based cell-cell adhesions and driven by Src and FAK activity. We demonstrate that the loss of cell-matrix adhesions near the Contact leads to a buildup of tension across the cell-cell Contact, a step that is essential to drive cell-cell separation after collision.
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michael abercrombie Contact Inhibition of locomotion and more
The International Journal of Developmental Biology, 2018Co-Authors: Alice Roycroft, Roberto MayorAbstract:Michael Abercrombie is regarded as one of the principal pioneers of cell biology. Although Abercrombie began his career as an experimental embryologist, working on the avian organizer with C. H. Waddington, questions on how cells in culture migrate and interact dominated his career. Whilst studying the social behaviour of chick heart embryonic fibroblasts, Abercrombie identified a phenomenon whereby colliding cells collapse their protrusions towards the cell-cell Contact upon a collision, preventing their continued migration. The cells then form protrusions away from the Contact and, space permitting, migrate away from each other. This behaviour is now referred to as 'Contact Inhibition of locomotion' and has been identified within embryology as the driving force behind the directional migration of the neural crest and the dispersion patterning of haemocytes and Cajal-Retzius neurons. Furthermore, its loss between collisions of cancer cells and healthy cells is associated with metastasis. In this review we begin with an overview of Abercrombie's life and highlight some of his key publications. We then discuss Abercrombie's discovery of Contact Inhibition of locomotion, the roles which cell-cell adhesions, cell-matrix adhesions and the cytoskeleton play in facilitating this phenomenon, and the importance of Contact Inhibition of locomotion within the living organism.
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pdgf controls Contact Inhibition of locomotion by regulating n cadherin during neural crest migration
Development, 2017Co-Authors: Isabel Bahm, Eric Theveneau, Elias H Barriga, Antonina Frolov, Paul Frankel, Roberto MayorAbstract:A fundamental property of neural crest (NC) migration is Contact Inhibition of locomotion (CIL), a process by which cells change their direction of migration upon cell Contact. CIL has been proven to be essential for NC migration in amphibians and zebrafish by controlling cell polarity in a cell Contact-dependent manner. Cell Contact during CIL requires the participation of the cell adhesion molecule N-cadherin, which starts to be expressed by NC cells as a consequence of the switch between E- and N-cadherins during epithelial-to-mesenchymal transition (EMT). However, the mechanism that controls the upregulation of N-cadherin remains unknown. Here, we show that platelet-derived growth factor receptor alpha (PDGFRα) and its ligand platelet-derived growth factor A (PDGF-A) are co-expressed in migrating cranial NC. Inhibition of PDGF-A/PDGFRα blocks NC migration by inhibiting N-cadherin and, consequently, impairing CIL. Moreover, we identify phosphatidylinositol-3-kinase (PI3K)/AKT as a downstream effector of the PDGFRα cellular response during CIL. Our results lead us to propose PDGF-A/PDGFRα signalling as a tissue-autonomous regulator of CIL by controlling N-cadherin upregulation during EMT. Finally, we show that once NC cells have undergone EMT, the same PDGF-A/PDGFRα works as an NC chemoattractant, guiding their directional migration.
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mechanisms and in vivo functions of Contact Inhibition of locomotion
Nature Reviews Molecular Cell Biology, 2017Co-Authors: Brian Stramer, Roberto MayorAbstract:Contact Inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis.
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Molecular basis of Contact Inhibition of locomotion
Cellular and Molecular Life Sciences, 2016Co-Authors: Alice Roycroft, Roberto MayorAbstract:Contact Inhibition of locomotion (CIL) is a complex process, whereby cells undergoing a collision with another cell cease their migration towards the colliding cell. CIL has been identified in numerous cells during development including embryonic fibroblasts, neural crest cells and haemocytes and is the driving force behind a range of phenomenon including collective cell migration and dispersion. The loss of normal CIL behaviour towards healthy tissue has long been implicated in the invasion of cancer cells. CIL is a multi-step process that is driven by the tight coordination of molecular machinery. In this review, we shall breakdown CIL into distinct steps and highlight the key molecular mechanisms and components that are involved in driving each step of this process.
Douglas C Dean - One of the best experts on this subject based on the ideXlab platform.
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mouse fibroblasts lacking rb1 function form spheres and undergo reprogramming to a cancer stem cell phenotype
Cell Stem Cell, 2009Co-Authors: Brian Clem, Ewa K Zubasurma, Shahenda Elnaggar, Sucheta Telang, A B Jenson, Yali Wang, Hui Shao, Mariusz Z Ratajczak, Jason Chesney, Douglas C DeanAbstract:Summary Activation of the RB1 pathway triggers the cell-cycle arrest that mediates cell-cell Contact Inhibition. Accordingly, mutation of all three RB1 family members leads to loss of Contact Inhibition and outgrowth of fibroblasts into spheres where cell-cell Contacts predominate. We present evidence that such outgrowth triggers reprogramming to generate cells with properties of cancer stem cells. Fibroblasts with only a single RB1 mutation remain Contact inhibited; however, if this Contact Inhibition is bypassed by forcing the RB1 −/− cells to form spheres in suspension, cells with properties of cancer stem cells are also generated. These cells not only form tumors in nude mice but also generate differentiated cells. We propose that Contact Inhibition imposed by the RB1 pathway performs an unexpected tumor suppressor function by preventing cell outgrowth into structures where cells with properties of cancer stem cells can be generated from differentiated somatic cells in advancing cancers.
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active transcriptional repression by the rb e2f complex mediates g1 arrest triggered by p16ink4a tgfβ and Contact Inhibition
Cell, 1999Co-Authors: Steven H Zhang, Antonio Postigo, Douglas C DeanAbstract:Abstract Rb inhibits progression from G1 to S phase of the cell cycle. It associates with a number of cellular proteins; however, the nature of these interactions and their relative significance in cell cycle regulation are still unclear. We present evidence that Rb must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the Rb–E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. We demonstrate that active repression by Rb–E2F mediates the G1 arrest triggered by TGFβ, p16 INK4a , and Contact Inhibition.
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active transcriptional repression by the rb e2f complex mediates g1 arrest triggered by p16ink4a tgfβ and Contact Inhibition
Cell, 1999Co-Authors: Steven H Zhang, Antonio Postigo, Douglas C DeanAbstract:Rb inhibits progression from G1 to S phase of the cell cycle. It associates with a number of cellular proteins; however, the nature of these interactions and their relative significance in cell cycle regulation are still unclear. We present evidence that Rb must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the Rb-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. We demonstrate that active repression by Rb-E2F mediates the G1 arrest triggered by TGFbeta, p16INK4a, and Contact Inhibition.
Eric Theveneau - One of the best experts on this subject based on the ideXlab platform.
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pdgf controls Contact Inhibition of locomotion by regulating n cadherin during neural crest migration
Development, 2017Co-Authors: Isabel Bahm, Eric Theveneau, Elias H Barriga, Antonina Frolov, Paul Frankel, Roberto MayorAbstract:A fundamental property of neural crest (NC) migration is Contact Inhibition of locomotion (CIL), a process by which cells change their direction of migration upon cell Contact. CIL has been proven to be essential for NC migration in amphibians and zebrafish by controlling cell polarity in a cell Contact-dependent manner. Cell Contact during CIL requires the participation of the cell adhesion molecule N-cadherin, which starts to be expressed by NC cells as a consequence of the switch between E- and N-cadherins during epithelial-to-mesenchymal transition (EMT). However, the mechanism that controls the upregulation of N-cadherin remains unknown. Here, we show that platelet-derived growth factor receptor alpha (PDGFRα) and its ligand platelet-derived growth factor A (PDGF-A) are co-expressed in migrating cranial NC. Inhibition of PDGF-A/PDGFRα blocks NC migration by inhibiting N-cadherin and, consequently, impairing CIL. Moreover, we identify phosphatidylinositol-3-kinase (PI3K)/AKT as a downstream effector of the PDGFRα cellular response during CIL. Our results lead us to propose PDGF-A/PDGFRα signalling as a tissue-autonomous regulator of CIL by controlling N-cadherin upregulation during EMT. Finally, we show that once NC cells have undergone EMT, the same PDGF-A/PDGFRα works as an NC chemoattractant, guiding their directional migration.
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cadherin switch during emt in neural crest cells leads to Contact Inhibition of locomotion via repolarization of forces
Developmental Cell, 2015Co-Authors: Elena Scarpa, Andras Szabo, Maddy Parsons, Eric Theveneau, Anne Bibonne, Roberto MayorAbstract:Contact Inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell Contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in Contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.
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the role of the non canonical wnt planar cell polarity pathway in neural crest migration
Biochemical Journal, 2014Co-Authors: Roberto Mayor, Eric TheveneauAbstract:The neural crest is an embryonic stem cell population whose migratory behaviour has been likened to malignant invasion. The neural crest, as does cancer, undergoes an epithelial-to-mesenchymal transition and migrates to colonize almost all the tissues of the embryo. Neural crest cells exhibit collective cell migration, moving in streams of high directionality. The migratory neural crest streams are kept in shape by the presence of negative signals in their vicinity. The directionality of the migrating neural crest is achieved by Contact-dependent cell polarization, in a phenomenon called Contact Inhibition of locomotion. Two cells experiencing Contact Inhibition of locomotion move away from each other after collision. However, if the cell density is high only cells exposed to a free edge can migrate away from the cluster leading to the directional migration of the whole group. Recent work performed in chicks, zebrafish and frogs has shown that the non-canonical Wnt–PCP (planar cell polarity) pathway plays a major role in neural crest migration. PCP signalling controls Contact Inhibition of locomotion between neural crest cells by localizing different PCP proteins at the site of cell Contact during collision and locally regulating the activity of Rho GTPases. Upon collision RhoA (ras homologue family member A) is activated, whereas Rac1 is inhibited at the Contact between two migrating neural crest cells, leading to the collapse of protrusions and the migration of cells away from one another. The present review summarizes the mechanisms that control neural crest migration and focuses on the role of non-canonical Wnt or PCP signalling in this process.
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par3 controls neural crest migration by promoting microtubule catastrophe during Contact Inhibition of locomotion
Development, 2013Co-Authors: Rachel Moore, Madeline Parsons, Eric Theveneau, Jubin Kashef, Sara Pozzi, Paula Alexandre, Joanna Richardson, Anne Merks, Claudia Linker, Roberto MayorAbstract:There is growing evidence that Contact Inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell Contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell Contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double Inhibition of Par3 and Trio restores microtubule catastrophe at the cell Contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.
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a novel method to study Contact Inhibition of locomotion using micropatterned substrates
Biology Open, 2013Co-Authors: Elena Scarpa, Alice Roycroft, Eric Theveneau, Emmanuel Terriac, Matthieu Piel, Roberto MayorAbstract:The concept of Contact Inhibition of locomotion (CIL) describes the ability of a cell to change the direction of its movement after Contact with another cell. It has been shown to be responsible for physiological and developmental processes such as wound healing, macrophage dispersion and neural crest cell migration; whereas its loss facilitates cancer cell invasion and metastatic dissemination. Different assays have been developed to analyze CIL in tissue culture models. However, these methods have several caveats. Collisions happen at low frequency between freely migrating cells and the orientation of the cells at the time of Contact is not predictable. Moreover, the computational analysis required by these assays is often complicated and it retains a certain degree of discretion. Here, we show that confinement of neural crest cell migration on a single dimension by using a micropatterned substrate allows standardized and predictable cell–cell collision. CIL can thus easily be quantified by direct measurement of simple cellular parameters such as the distance between nuclei after collision. We tested some of the signaling pathways previously identified as involved in CIL, such as small GTPases and non-canonical Wnt signaling, using this new method for CIL analysis. The restricted directionality of migration of cells in lines is a powerful strategy to obtain higher predictability and higher efficiency of the CIL response upon cell–cell collisions.
Steven H Zhang - One of the best experts on this subject based on the ideXlab platform.
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active transcriptional repression by the rb e2f complex mediates g1 arrest triggered by p16ink4a tgfβ and Contact Inhibition
Cell, 1999Co-Authors: Steven H Zhang, Antonio Postigo, Douglas C DeanAbstract:Abstract Rb inhibits progression from G1 to S phase of the cell cycle. It associates with a number of cellular proteins; however, the nature of these interactions and their relative significance in cell cycle regulation are still unclear. We present evidence that Rb must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the Rb–E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. We demonstrate that active repression by Rb–E2F mediates the G1 arrest triggered by TGFβ, p16 INK4a , and Contact Inhibition.
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active transcriptional repression by the rb e2f complex mediates g1 arrest triggered by p16ink4a tgfβ and Contact Inhibition
Cell, 1999Co-Authors: Steven H Zhang, Antonio Postigo, Douglas C DeanAbstract:Rb inhibits progression from G1 to S phase of the cell cycle. It associates with a number of cellular proteins; however, the nature of these interactions and their relative significance in cell cycle regulation are still unclear. We present evidence that Rb must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the Rb-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. We demonstrate that active repression by Rb-E2F mediates the G1 arrest triggered by TGFbeta, p16INK4a, and Contact Inhibition.
Carlos Carmonafontaine - One of the best experts on this subject based on the ideXlab platform.
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complement fragment c3a controls mutual cell attraction during collective cell migration
Developmental Cell, 2011Co-Authors: Carlos Carmonafontaine, Madeline Parsons, Eric Theveneau, Apostolia Tzekou, Masazumi Tada, Mae Woods, Karen M Page, John D Lambris, Roberto MayorAbstract:Collective cell migration is a mode of movement crucial for morphogenesis and cancer metastasis. However, little is known about how migratory cells coordinate collectively. Here we show that mutual cell-cell attraction (named here coattraction) is required to maintain cohesive clusters of migrating mesenchymal cells. Coattraction can counterbalance the natural tendency of cells to disperse via mechanisms such as Contact Inhibition and epithelial-to-mesenchymal transition. Neural crest cells are coattracted via the complement fragment C3a and its receptor C3aR, revealing an unexpected role of complement proteins in early vertebrate development. Loss of coattraction disrupts collective and coordinated movements of these cells. We propose that coattraction and Contact Inhibition act in concert to allow cell collectives to self-organize and respond efficiently to external signals, such as chemoattractants and repellents.
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keeping in touch with Contact Inhibition of locomotion
Trends in Cell Biology, 2010Co-Authors: Roberto Mayor, Carlos CarmonafontaineAbstract:Contact Inhibition of locomotion (CIL) is the process by which cells in vitro change their direction of migration upon Contact with another cell. Here, we revisit the concept that CIL plays a central role in the migration of single cells and in collective migration, during both health and disease. Importantly, malignant cells exhibit a diminished CIL behaviour which allows them to invade healthy tissues. Accumulating evidence indicates that CIL occurs in vivo and that regulation of small Rho GTPases is important in the collapse of cell protrusions upon cell Contact, the first step of CIL. Finally, we propose possible cell surface proteins that could be involved in the initial Contact that regulates Rho GTPases during CIL.
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Contact Inhibition of locomotion in vivo controls neural crest directional migration
Nature, 2008Co-Authors: Carlos Carmonafontaine, Sei Kuriyama, Graham Dunn, Helen K Matthews, Mauricio Moreno, Madeline Parsons, Claudio D Stern, Roberto MayorAbstract:The phenomenon of Contact Inhibition of cell movement (or locomotion) was first identified more than 50 years ago in fibroblast cells in vitro, and defective Contact Inhibition is suggested as a factor in malignant cell invasiveness. It occurs when two cells touch; they retract their protrusions and change their direction of movement. But the molecular basis of this Inhibition, and whether it happens in vivo, are still matters of controversy. Now time-lapse microscopy of neural crest cells, highly migratory cells of embryonic origin, has been used to demonstrate Contact Inhibition of locomotion both in vivo and in vitro, and that it can account for their directional migration. But when a neural crest cell meets another cell type it fails to display Contact Inhibition of locomotion, allowing it to invade the tissue. This paper studies a phenomenon called Contact Inhibition of locomotion, whereby fibroblast cells grown in cell culture retract their protrusions and change their direction on Contact. It is shown that this occurs in vivo, and the molecular basis is revealed. Neural crest cells, highly migratory cells of embryonic origin, exhibit Contact Inhibition of locomotion both in vivo and in vitro, which accounts for their directional migration. However, when a neural crest cell meets another cell type, it fails to display Contact Inhibition of locomotion, allowing it to invade the tissue. Contact Inhibition of locomotion was discovered by Abercrombie more than 50 years ago and describes the behaviour of fibroblast cells confronting each other in vitro, where they retract their protrusions and change direction on Contact1,2. Its failure was suggested to contribute to malignant invasion3,4,5,6. However, the molecular basis of Contact Inhibition of locomotion and whether it also occurs in vivo are still unknown. Here we show that neural crest cells, a highly migratory and multipotent embryonic cell population, whose behaviour has been likened to malignant invasion6,7,8, demonstrate Contact Inhibition of locomotion both in vivo and in vitro, and that this accounts for their directional migration. When two migrating neural crest cells meet, they stop, collapse their protrusions and change direction. In contrast, when a neural crest cell meets another cell type, it fails to display Contact Inhibition of locomotion; instead, it invades the other tissue, in the same manner as metastatic cancer cells3,5,9. We show that Inhibition of non-canonical Wnt signalling abolishes both Contact Inhibition of locomotion and the directionality of neural crest migration. Wnt-signalling members localize at the site of cell Contact, leading to activation of RhoA in this region. These results provide the first example of Contact Inhibition of locomotion in vivo, provide an explanation for coherent directional migration of groups of cells and establish a previously unknown role for non-canonical Wnt signalling.
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Contact Inhibition of locomotion in vivo controls neural crest directional migration
Nature, 2008Co-Authors: Carlos Carmonafontaine, Sei Kuriyama, Graham Dunn, Helen K Matthews, Mauricio Moreno, Madeline Parsons, Claudio D Stern, Roberto MayorAbstract:Contact Inhibition of Locomotion was discovered by Abercrombie more than 50 years ago to describe the behaviour of fibroblast cells confronting each other in vitro, where they retract their protrusions and change direction upon Contact1,2. Its failure was suggested to contribute to malignant invasion3-6. However, the molecular basis of Contact Inhibition of Locomotion and whether it also occurs in vivo are still unknown. Here we show that neural crest cells, a highly migratory and multipotent embryonic cell population, whose behaviour has been likened to malignant invasion6-8, exhibit Contact Inhibition of Locomotion both in vivo and in vitro, and that this accounts for their directional migration. When two migrating neural crest cells meet, they stop, collapse their protrusions and change direction. In contrast, when a neural crest cell meets another cell type, it fails to display Contact Inhibition of Locomotion; instead, it invades the other tissue, like metastatic cancer cells3,5,9. We show that Inhibition of non-canonical Wnt signalling abolishes both Contact Inhibition of Locomotion and the directionality of neural crest migration. Wnt signalling members localise at the site of cell Contact, leading to activation of RhoA in this region. These results provide the first example of Contact Inhibition of Locomotion in vivo, present an explanation for coherent directional migration of group of cells and establish a novel role for non-canonical Wnt signalling.