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The PDGF/VEGF signaling superfamily. PDGFRs (A), PDGFs (B) and related proteins (A,B) identified in different organisms. Vertebrate VEGFs and VEGFRs are not included in this figure, but a prototypical mammalian VEGFR is shown for comparison (A). Mouse, human, Drosophila and C. elegans proteins are discussed in the text (see text for references). In some teleosts, including zebrafish and pufferfish, the Pdgfrb genomic locus appears to have been duplicated, giving these species three PDGF receptors, PDGFRα, PDGFRβ1.1, and PDGFRβ1.2 (Williams et al., 2002). There are three known splice variants of chick PDGFA, which correspond to the short and long forms identified in mouse, as well as an additional short form (Ataliotis, 2000; Hamada et al., 2000; Horiuchi et al., 2001). Only one receptor (PDGFRα) and two splice variants of PDGFA have been identified in Xenopus (Mercola et al., 1988; Bejcek et al., 1990; Jones et al., 1993). C. elegans and Drosophila melanogaster each have a single PDGF/VEGF-like signaling network. C. elegans has four VEGFR-like proteins, VER-1 to VER-4, but no definitive VER ligand has been identified or characterized. Drosophila has three PDGF/VEGF ligands, PVF-1, 2 and 3, and one receptor, PVR. Two splice forms of PVF-1 have been identified that differ at their N termini. Three splice variants of PVR have also been identified: two differ in the region between the second and third immunoglobulin (Ig) domains, and the third is truncated after the second Ig domain. Mm, Mus musculus (mouse); Hs, Homo sapiens (human); Dr, Danio rerio (zebrafish); Gg, Gallus gallus (chick); Xl, Xenopus laevis (frog); Dm, Drosophila melanogaster (fruit fly); Ce, Caenorhabditis elegans (nematode).
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Mammalian PDGF/PDGFR binding interactions. The ability of different homo- and heterodimeric PDGF ligands to bind the different receptor dimers in vitro is shown. Arrows between ligands and receptors indicate the ability of a given ligand dimer to bind to and activate the designated receptor. PDGF dimers are represented by the letters of their constituent subunits, for example, AA is a PDGFA homodimer, and AB is a heterodimer of PDGFA and PDGFB.
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Signal transduction downstream of activated PDGFRs. Upon ligand binding, PDGFRs dimerize, activate intracellular tyrosine kinase domains, and autophosphorylate several tyrosine residues to generate docking sites for signaling and adaptor proteins. Proteins that interact with activated (ligand-bound) mammalian PDGFRα and PDGFRβ homodimers are shown. Also indicated are the signaling pathways activated by the receptor-binding proteins (reviewed by Heldin and Westermark, 1999). Stat5, Signal transducer and activator of transcription 5; PI3K, phosphatidylinositol 3-kinase; SHP2, SH2-containing protein tyrosine phosphatase; PLCγ, phospholipase Cγ; JNK, Jun N-terminal kinase; SAPK, stress activated protein kinase; p70S6K, p70 S6 kinase; PKB, protein kinase B; PKC, protein kinase C; MAPK, mitogen activated protein kinase; RasGAP, Ras GTPase-activating protein.
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Roles of PDGF in the developing nervous and circulatory systems. (A) Oligodendrocyte precursor cell development in the mouse spinal cord. Oligodendrocyte precursor (O2A) cells, which express PDGFRα, arise in the ventral periventricular zone of the mouse embryonic neural tube around E12.5. From E12.5-E15.5, O2A cells proliferate and migrate laterally and dorsally to fill the spinal cord. During this time, PDGFA is expressed by neurons and astrocytes in the spinal cord, and PDGFC is expressed by cells in the floor plate and ventral horn regions. There is evidence that PDGFA/PDGFRα signaling drives O2A cell proliferation in the spinal cord (E12.5-E15.5). PDGFRα signaling may also influence the migration of O2A cells. The general migration route taken by O2A progenitors is depicted by gray arrows. (B) Vascular mural cell proliferation and migration in the mouse. During angiogenesis, primitive vascular networks (or plexa) are remodeled through branching, sprouting, and pruning of the vascular endothelium. As new vessels form, they recruit and are coated by mural cells, contractile cells that support and stabilize new vessels. The two major classes of vascular mural cells are pericytes, which form single cell layers around capillaries, and vascular smooth muscle cells (VSMCs), which coat veins and arteries. During angiogenic remodeling, PDGFB is expressed in nascent vascular endothelial sprouts (a) and drives the proliferation of PDGFRβ-expressing pericytes and VSMCs near arterial walls and primitive vascular plexa (b). PDGFB also directs the migration and/or survival of these mural cells along endothelial sprouts (b,c). Upon reaching their destination, VSMCs and pericytes encircle and associate tightly with the endothelium (c); survival and anti-proliferative factors produced by mural cells stabilize nascent vessels.
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PVF/PVR signals direct cell migration during Drosophila development. (A) Hemocyte migration. Hemocytes (red) originate as bilateral clusters in the anterior region of Drosophila embryos. These cells migrate anteriorly, posteriorly and ventrally to populate the wild-type embryo (red arrows indicate migration routes). PVF ligands are expressed along the embryonic hemocyte migration routes and guide or enable hemocyte migration: in Pvr mutant or Pvf1, 2, 3 knockdown embryos, hemocytes cluster in the head region and fail to enter the caudal region of the embryo. (B) Border cell cluster migration in response to PVF1. In the left-most panel, a stage 9 Drosophila egg chamber expressing lacZ in border cells is stained with anti-β-galactosidase (green; border cells) and phalloidin (red; actin), and shows a long cellular extension (LCE; white arrow), which protrudes from one cell of the border cell cluster toward the oocyte. PVF1 is expressed by oocytes in Drosophila egg chambers, and PVR is expressed by all follicle cells, including the border cell cluster (red, green). In response to a graded PVF1 signal (blue), one border cell of the cluster protrudes a long cellular extension (LCE, green) toward the source of PVF1. This LCE guides the migration of the border cell cluster from the anterior cortex of the egg chamber to its final posterior location next to the oocyte. The panel on the left is copied with permission from Fulga and Rørth (Fulga and Rørth, 2002). Scale bar: 20 μm.
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PDGF roles in mammalian organogenesis. In several early developmental contexts, epithelial PDGF drives proliferation of undifferentiated mesenchyme expressing PDGFRα. However, during organ maturation, PDGF signals direct several other cellular functions. (See text for more details.) (A) Cell migration and angiogenesis. In the developing kidney, PDGFB/PDGFRβ signaling is essential for the migration of Pdgfrb-expressing endothelial/mesangial cell precursors (blue) from (a) the cleft of the S-shaped nephron into (b,c) the glomerular space. These cells give rise to the glomerular capillary bed (red) and its mesangial cells (pericyte-like cells that coat glomerular capillaries; c). (d) In Pdgfb- and Pdgfrb-null embryos, few Pdgfrb-expressing precursors migrate to the nephron cleft, and these cells fail to enter the glomerular space; capillary beds fail to form in these embryos and capillary aneurysms are observed in the glomerular space. The embryonic testis vasculature develops through the formation of the coelomic vessel (a′, b′) and the branching of this vessel between testis cords (c′). Endothelial cells (blue) migrate from the mesonephros into the testis, where they contribute to the coelomic vessel and its branches (red). PDGFRα is required for both endothelial cell migration and branching of the coelomic vessel. In both the kidney and testis, PDGF signals may directly induce angiogenic branching of the primitive vasculature, although this has not been clearly shown in vivo. (B) Cellular differentiation and/or function. PDGF signals are essential for the differentiation and/or function of interstitial cell types in the developing testis. PDGFRα is required for the differentiation of both fetal and adult Leydig cells. The ligand(s) required for fetal Leydig cell development are not yet known, but PDGFA is required for the development of adult Leydig cells, which replace fetal Leydig cells during postnatal testis maturation. There is evidence from in vitro studies that PDGF signals may induce perimyoid cell (PMC) differentiation and/or function. These cells originate in the interstitium and differentiate into contractile, smooth muscle-like cells that associate tightly with testis cords. Together, PMCs and Sertoli cells produce the basement membrane around cords. The source(s) of PDGFs that direct interstitial cell differentiation/function is not clear, although PDGFs are secreted from the coelomic vessel, the mesonephros and testis cords. (C) Epithelial folding. Pdgfra-expressing mesenchymal cells cluster at sites of future epithelial folding during lung, skin and intestine morphogenesis. Although the Pdgfra-expressing cells are essential for these morphogenetic processes, their roles and the role(s) of PDGF signaling in folding morphogenesis are not yet known. Late in embryogenesis, Pdgfra-positive mesenchymal cells (blue) in the lung migrate to sites of alveolar septation (a), a postnatal process in which the air sac epithelium invaginates and is lined with specialized matrix. Septation does not occur in the absence of the Pdgfra-positive cells, whose development requires PDGFA during embryogenesis. During intestine maturation, Pdgfra-positive mesenchymal cells (blue) cluster at sites of future villus formation (b). The intestinal epithelium subsequently folds into the lumen of the intestine and Pdgfra-positive cells migrate from the clusters to line the forming villus. Pdgfra expression is maintained in these cells during villus maturation, and, in PDGFA-null mice, villus structure and epithelial differentiation are abnormal.
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