NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells

Fantin, Alessandro; Lampropoulou, Anastasia; Gestri, Gaia; Raimondi, Claudio; Senatore, Valentina; Zachary, Ian; Ruhrberg, Christiana

doi:10.1016/j.celrep.2015.11.049

Cited by 14 publications

(18 citation statements)

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“…Phalloidin staining of F-actin revealed NRP2 siRNA treated ECs adhered to FN for either 90 or 180 minutes exhibited a rounded morphology with visibly fewer stress fibres, and localisation of actin fibres to rings at the cell periphery compared to control siRNA treated ECs (Fig2C). This phenotype is characteristic of low motility, and is reminiscent of that observed by Fantin et al in hMVECs following NRP1 knockdown, in addition to a significantly reduced number of actin positive, filopodia-like microspikes [34]. Finally, to directly assess how these changes to FAs and the actin cytoskeleton might affect the ability of mLMECs to adhere to FN, we compared the relative number of cells adhered to 96-well plates pre-coated with FN for either 15 or 30 minutes.…”

Section: Depletion Of Nrp2 In Ecs Disrupts Adhesion To Fn Matricessupporting

confidence: 71%

NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrin

Alghamdi

Benwell

Atkinson

et al. 2019

Preprint

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Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood.Here we demonstrate that NRP2 promotes EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on β3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organisation. Finally, we propose a mechanism whereby NRP2 regulates ITGA5 trafficking in ECs by promoting Rab11-dependent recycling of ITGA5. NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs, where we demonstrate a strong co-localisation between NRP2, ITGA5 and Rab11. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN.

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Section: Depletion Of Nrp2 In Ecs Disrupts Adhesion To Fn Matricessupporting

confidence: 71%

NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrin

Alghamdi

Benwell

Atkinson

et al. 2019

Preprint

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“…NRP-1 is a non-tyrosine kinase protein that acts as a VEGF receptor 2 co-receptor to modulate cell behaviour. NRP-1 plays an essential role in extracellular matrix-induced Cdc42 activation in endothelial cells by localizing Cdc42 to sites of actin branching in cytoskeletal remodelling and filopodial extension [41]. NRP-1 was decreased in the podocytes of db/db mice, and was also down-regulated in HG-treated podocytes in the present study, while NRP-1 was increased in NR1-shRNA-treated podocytes, but not influenced by the Cdc42 inhibitor ML141, demonstrating that NMDAR activation is associated with decreased NRP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes

Shen

Wang

et al. 2016

J. Pathol.

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Podocytes play important roles in the progression of diabetic kidney disease (DKD) and these roles are closely associated with cytoskeletal actin dynamics. N-Methyl-d-aspartate receptors (NMDARs), which consist of two functional NR1 subunits and two regulatory NR2 subunits, are widely expressed in the brain but are also found in podocytes. Here, we found increased NR1 expression in two diabetic mouse models and in podocytes incubated in high glucose (HG). In diabetic mice, knockdown of NR1 using lentivirus carrying NR1-shRNA ameliorated the pathological features associated with DKD, and reversed the decreased expression of synaptopodin and Wilms' tumour-1. In podocytes incubated with HG, NR1 was secreted from the endoplasmic reticulum and this was blocked by bisindolylmaleimide I. NR1 knockdown decreased the cell shape remodelling, cell collapse, bovine serum albumin permeability, and migration induced by HG. After HG incubation, levels of cell division control protein 42 (Cdc42) and its active form increased, and a significantly higher Cdc42-GTP level, increased Cdc42 translocation onto the leading edges, and lower migration ability were found in podocytes with NR1 knockdown. Increases in the number and length of filopodia were found in podocytes with NR1 knockdown but these were abolished by Cdc42-GTP blockade with ML141. In conclusion, the activation of NMDARs plays an important role in DKD by reducing Cdc42-GTP activation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…It is still possible that in other contexts, dynamic contacts also exist, but imaging in fixed tissue might have hampered their identification, as suggested by Obernier and colleagues 57 . Filopodia in angiogenic tip cells and migrating ECs have been described 40,[58][59][60] . To our knowledge, filopodia from endothelial stalk cells contacting neuronal cells have not been reported before.…”

Section: Discussionmentioning

confidence: 99%

Neuroblast sensory quiescence depends of vascular cytoneme contacts and sensory neuronal differentiation requires initiation of blood flow

Taberner

Bañón

Alsina

2019

Preprint

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Cranial sensory neurons develop in close proximity to blood vessels, however neurovascular interactions in the peripheral nervous system and their underlying signals are yet unknown.Here, we uncover two separate, novel roles for cranial vasculature in cranial sensory neurogenesis in zebrafish. The first involves precise spatiotemporal endothelial-neuroblast filopodial contacts and Dll4-Notch signaling to restrain neuroblast proliferation. Secondly, we find a role for signaling triggered by blood flow in promoting sensory neuron differentiation.Thus, we demonstrate that the cranial vasculature constitutes a hitherto unrecognized signaling component of the sensory ganglia niche and controls the pace of their growth and differentiation dynamics.

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NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells

Cited by 14 publications

References 0 publications

NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrin

NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrin

NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes

Neuroblast sensory quiescence depends of vascular cytoneme contacts and sensory neuronal differentiation requires initiation of blood flow

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