Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning

Gelfand, Maria V.; Hong, Shangyu; Gu, Chenghua

doi:10.1016/j.tcb.2009.01.001

Cited by 51 publications

(50 citation statements)

References 92 publications

(125 reference statements)

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“…Thus, Sema6A emerges as yet another example of a regulator of neuronal and vascular development. 50 Moreover, our findings identify Sema6A as a potential therapeutic target for ocular pathologies stemming from defective remodeling of hyaloid vessels, and for reducing tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 80%

Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

Segarra

Ohnuki

Maric

et al. 2012

Blood

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Formation of new vessels during development and in the mature mammal generally proceeds through angiogenesis. Although a variety of molecules and signaling pathways are known to underlie endothelial cell sprouting and remodeling during angiogenesis, many aspects of this complex process remain unexplained. Here we show that the transmembrane semaphorin6A (Sema6A) is expressed in endothelial cells, and regulates endothelial cell survival and growth by modulating the expression and signaling of VEGFR2, which is known to maintain endothelial cell viability by autocrine VEGFR signaling. The silencing of Sema6A in primary endothelial cells promotes cell death that is not rescued by exogenous VEGF-A or FGF2, attributable to the loss of prosurvival signaling from endogenous VEGF. Analyses of mouse tissues demonstrate that Sema6A is expressed in angiogenic and remodeling vessels. Mice with null mutations of Sema6A exhibit significant defects in hyaloid vessels complexity associated with increased endothelial cell death, and in retinal vessels development that is abnormally reduced. Adult Sema6A-null mice exhibit reduced tumor, matrigel, and choroidal angiogenesis compared with controls. Sema6A plays important roles in development of the nervous system. Here we show that it also regulates vascular development and adult angiogenesis. IntroductionAngiogenesis during development and in adult mammals proceeds largely through endothelial cell sprouting and sprouts remodeling to generate a network of vessels where blood can flow. VEGF-A, its receptor VEGFR2, and coreceptor neuropilin-1, Notch ligands, and Notch receptors, B-ephrin ligands, and EphB receptors, and other molecules are critical mediators of angiogenesis, but aspects of this process are not explained and other molecules probably contribute.The semaphorins comprise a family of membrane-bound and secreted proteins implicated in the development of the neural system, and in modulating immune responses and tumor growth in the adult. [1][2][3] Semaphorins are characterized by the presence of a Sema domain, a 500 residue N-terminal domain, structurally similar to the extracellular domain of ␣-integrins, and a determinant of receptor binding specificity. 4 There are 8 classes of semaphorins, including classes 1 and 2 found mostly in invertebrates, classes 3 to 7 found in vertebrates, and the viral (V) class encoded by viruses. Semaphorins signal through their plexin receptors, but whereas membrane-bound semaphorins bind directly to their cognate plexin receptors, the secreted class-3 semaphorins require neuropilin-1 or 2 as coreceptors. 5,6 Plexin receptors can elicit multiple signaling pathways in response to semaphorin activation, as they associate with various signaling protein partners. 6 Many secreted class-3 semaphorins have been reported to inhibit angiogenesis. 2 Semaphorin-3A (Sema-3A), which binds neuropilin-1 and signals through plexinA1, A2, or A4, inhibits endothelial cell responses to VEGF 165 in vitro. [7][8][9][10][11][12] However, it is not clear whether ...

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Section: Discussionmentioning

confidence: 80%

Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

Segarra

Ohnuki

Maric

et al. 2012

Blood

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“…The common targets of semaphorins are the actin cytoskeleton and focal adhesions; the latter are dynamic cell-to-extracellular matrix adhesive structures that are assembled upon integrin engagement. Semaphorin signaling affects focal adhesion assembly/disassembly and induces cytoskeletal remodeling, thus consequently affecting cell shape, attachment to the extracellular matrix, cell motility, and cell migration [12,13].…”

Section: Semaphorinsmentioning

confidence: 99%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro-and anti-angiogenic signals. While pro-angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

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“…EphB signaling plays an important role in several aspects of vascular remodeling during angiogenesis (Mosch et al, 2010), axon guidance (Bashaw and Klein), and neuronal patterning (Gelfand et al, 2009). EphB2/B3 receptors are also expressed in the pancreatic epithelium, and its ligands ephrin B1 and ephrinB2 expression are detected in the pancreatic mesenchyme (E12) and pancreatic arteries ($E11.5), respectively (van Eyll et al, 2006;Villasenor et al, 2010).…”

Section: Polarization and Tube Formation From The Protodifferentiatedmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning

Cited by 51 publications

References 92 publications

Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Pancreas organogenesis: From bud to plexus to gland

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