Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 307 (5707): 265-268

Copyright © 2005 by the American Association for the Advancement of Science

Semaphorin 3E and Plexin-D1 Control Vascular Pattern Independently of Neuropilins

Chenghua Gu,1,2* Yutaka Yoshida,3* Jean Livet,4 Dorothy V. Reimert,1,2 Fanny Mann,4 Janna Merte,1,2 Christopher E. Henderson,4 Thomas M. Jessell,3 Alex L. Kolodkin,1{dagger} David D. Ginty1,2{dagger}

Abstract: The development of a patterned vasculature is essential for normal organogenesis. We found that signaling by semaphorin 3E (Sema3E) and its receptor plexin-D1 controls endothelial cell positioning and the patterning of the developing vasculature in the mouse. Sema3E is highly expressed in developing somites, where it acts as a repulsive cue for plexin-D1–expressing endothelial cells of adjacent intersomitic vessels. Sema3E–plexin-D1 signaling did not require neuropilins, which were previously presumed to be obligate Sema3 coreceptors. Moreover, genetic ablation of Sema3E or plexin-D1 but not neuropilin-mediated Sema3 signaling disrupted vascular patterning. These findings reveal an unexpected semaphorin signaling pathway and define a mechanism for controlling vascular patterning.

1 The Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205–2185, USA.
2 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205–2185, USA.
3 Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
4 Institut National de la Santé et de la Recherche Médicale (INSERM), UMR623, Developmental Biology Institute of Marseille (IBDM), Marseille 13288, France.

Back to Top

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dginty{at} (D.D.G.); kolodkin{at} (A.L.K.)

Genetic dissection of plexin signaling in vivo.
T. Worzfeld, J. M. Swiercz, A. Senturk, B. Genz, A. Korostylev, S. Deng, J. Xia, M. Hoshino, J. A. Epstein, A. M. Chan, et al. (2014)
PNAS 111, 2194-2199
   Abstract »    Full Text »    PDF »
The LIM homeobox gene Isl1 is required for the correct development of the striatonigral pathway in the mouse.
L. A. Ehrman, X. Mu, R. R. Waclaw, Y. Yoshida, C. V. Vorhees, W. H. Klein, and K. Campbell (2013)
PNAS 110, E4026-E4035
   Abstract »    Full Text »    PDF »
The Plasma Proteome Identifies Expected and Novel Proteins Correlated with Micronutrient Status in Undernourished Nepalese Children.
R. N. Cole, I. Ruczinski, K. Schulze, P. Christian, S. Herbrich, L. Wu, L. R. DeVine, R. N. O'Meally, S. Shrestha, T. N. Boronina, et al. (2013)
J. Nutr. 143, 1540-1548
   Abstract »    Full Text »    PDF »
Endothelial RAF1/ERK activation regulates arterial morphogenesis.
Y. Deng, B. Larrivee, Z. W. Zhuang, D. Atri, F. Moraes, C. Prahst, A. Eichmann, and M. Simons (2013)
Blood 121, 3988-3996
   Abstract »    Full Text »    PDF »
Neuroimmune Guidance Cue Semaphorin 3E Is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention.
A. Wanschel, T. Seibert, B. Hewing, B. Ramkhelawon, T. D. Ray, J. M. van Gils, K. J. Rayner, J. E. Feig, E. R. O'Brien, E. A. Fisher, et al. (2013)
Arterioscler Thromb Vasc Biol 33, 886-893
   Abstract »    Full Text »    PDF »
Integration of Opposing Semaphorin Guidance Cues in Cortical Axons.
T. Ruediger, G. Zimmer, S. Barchmann, V. Castellani, D. Bagnard, and J. Bolz (2013)
Cereb Cortex 23, 604-614
   Abstract »    Full Text »    PDF »
Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone.
B. Saha, A. R. Ypsilanti, C. Boutin, H. Cremer, and A. Chedotal (2012)
J. Neurosci. 32, 16892-16905
   Abstract »    Full Text »    PDF »
Developing T-cell migration: role of semaphorins and ephrins.
D. A. Mendes-da-Cruz, M. A. Stimamiglio, J. J. Munoz, D. Alfaro, E. Terra-Granado, J. Garcia-Ceca, L. M. Alonso-Colmenar, W. Savino, and A. G. Zapata (2012)
FASEB J 26, 4390-4399
   Abstract »    Full Text »    PDF »
Semaphorins and neuropilins: new players in the neuroendocrine control of the intrathymic T-cell migration in humans.
D. A. Mendes-da-Cruz, L. Linhares-Lacerda, S. Smaniotto, M. Dardenne, and W. Savino (2012)
Exp Physiol 97, 1146-1150
   Abstract »    Full Text »    PDF »
Vascular Development in the Zebrafish.
A. V. Gore, K. Monzo, Y. R. Cha, W. Pan, and B. M. Weinstein (2012)
Cold Spring Harb Perspect Med 2, a006684
   Abstract »    Full Text »    PDF »
Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages.
C. Meda, F. Molla, M. De Pizzol, D. Regano, F. Maione, S. Capano, M. Locati, A. Mantovani, R. Latini, F. Bussolino, et al. (2012)
J. Immunol. 188, 4081-4092
   Abstract »    Full Text »    PDF »
Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.
A. Casazza, B. Kigel, F. Maione, L. Capparuccia, O. Kessler, E. Giraudo, M. Mazzone, G. Neufeld, and L. Tamagnone (2012)
EMBO Mol Med. 4, 234-250
   Abstract »    Full Text »    PDF »
MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A.
C. Urbich, D. Kaluza, T. Fromel, A. Knau, K. Bennewitz, R. A. Boon, A. Bonauer, C. Doebele, J.-N. Boeckel, E. Hergenreider, et al. (2012)
Blood 119, 1607-1616
   Abstract »    Full Text »    PDF »
Integration of Repulsive Guidance Cues Generates Avascular Zones That Shape Mammalian Blood Vessels.
S. M. Meadows, P. J. Fletcher, C. Moran, K. Xu, G. Neufeld, S. Chauvet, F. Mann, P. A. Krieg, and O. Cleaver (2012)
Circ. Res. 110, 34-46
   Abstract »    Full Text »    PDF »
Semaphorins in Angiogenesis and Tumor Progression.
G. Neufeld, A. D. Sabag, N. Rabinovicz, and O. Kessler (2012)
Cold Spring Harb Perspect Med 2, a006718
   Abstract »    Full Text »    PDF »
Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling.
B. Kigel, N. Rabinowicz, A. Varshavsky, O. Kessler, and G. Neufeld (2011)
Blood 118, 4285-4296
   Abstract »    Full Text »    PDF »
Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein.
A. Sakurai, X. Jian, C. J. Lee, Y. Manavski, E. Chavakis, J. Donaldson, P. A. Randazzo, and J. S. Gutkind (2011)
J. Biol. Chem. 286, 34335-34345
   Abstract »    Full Text »    PDF »
Structural Basis of Rnd1 Binding to Plexin Rho GTPase Binding Domains (RBDs).
H. Wang, P. K. Hota, Y. Tong, B. Li, L. Shen, L. Nedyalkova, S. Borthakur, S. Kim, W. Tempel, M. Buck, et al. (2011)
J. Biol. Chem. 286, 26093-26106
   Abstract »    Full Text »    PDF »
The {kappa} opioid system regulates endothelial cell differentiation and pathfinding in vascular development.
K. Yamamizu, S. Furuta, S. Katayama, M. Narita, N. Kuzumaki, S. Imai, H. Nagase, T. Suzuki, M. Narita, and J. K. Yamashita (2011)
Blood 118, 775-785
   Abstract »    Full Text »    PDF »
Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism.
J. Kim, W.-J. Oh, N. Gaiano, Y. Yoshida, and C. Gu (2011)
Genes & Dev. 25, 1399-1411
   Abstract »    Full Text »    PDF »
Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue.
K. H. Minor, J. C. Bournat, N. Toscano, R. J. Giger, and S. J. A. Davies (2011)
Brain 134, 1140-1155
   Abstract »    Full Text »    PDF »
Differential Endothelial Transcriptomics Identifies Semaphorin 3G as a Vascular Class 3 Semaphorin.
S. Kutschera, H. Weber, A. Weick, F. De Smet, G. Genove, M. Takemoto, C. Prahst, M. Riedel, C. Mikelis, S. Baulande, et al. (2011)
Arterioscler Thromb Vasc Biol 31, 151-159
   Abstract »    Full Text »    PDF »
An anteroposterior wave of vascular inhibitor downregulation signals aortae fusion along the embryonic midline axis.
R. J. Garriock, C. Czeisler, Y. Ishii, A. M. Navetta, and T. Mikawa (2010)
Development 137, 3697-3706
   Abstract »    Full Text »    PDF »
Semaphorin 3E Initiates Antiangiogenic Signaling through Plexin D1 by Regulating Arf6 and R-Ras.
A. Sakurai, J. Gavard, Y. Annas-Linhares, J. R. Basile, P. Amornphimoltham, T. R. Palmby, H. Yagi, F. Zhang, P. A. Randazzo, X. Li, et al. (2010)
Mol. Cell. Biol. 30, 3086-3098
   Abstract »    Full Text »    PDF »
A Forward Genetic Screen in Mice Identifies Sema3AK108N, which Binds to Neuropilin-1 but Cannot Signal.
J. Merte, Q. Wang, C. W. Vander Kooi, S. Sarsfield, D. J. Leahy, A. L. Kolodkin, and D. D. Ginty (2010)
J. Neurosci. 30, 5767-5775
   Abstract »    Full Text »    PDF »
Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development.
K. J. Reidy, G. Villegas, J. Teichman, D. Veron, W. Shen, J. Jimenez, D. Thomas, and A. Tufro (2009)
Development 136, 3979-3989
   Abstract »    Full Text »    PDF »
Role of Class 3 Semaphorins and Their Receptors in Tumor Growth and Angiogenesis.
P. Gaur, D. R. Bielenberg, S. Samuel, D. Bose, Y. Zhou, M. J. Gray, N. A. Dallas, F. Fan, L. Xia, J. Lu, et al. (2009)
Clin. Cancer Res. 15, 6763-6770
   Abstract »    Full Text »    PDF »
Somitovasculin, a Novel Endothelial-Specific Transcript Involved in the Vasculature Development.
D. Mariappan, R. Niemann, M. Gajewski, J. Winkler, S. Chen, S. Choorapoikayil, M. Bitzer, H. Schulz, J. Hescheler, and A. Sachinidis (2009)
Arterioscler Thromb Vasc Biol 29, 1823-1829
   Abstract »    Full Text »    PDF »
A new role for satellite cells: control of reinnervation after muscle injury by semaphorin 3A. Focus on "Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation".
L. K. McLoon (2009)
Am J Physiol Cell Physiol 297, C227-C230
   Full Text »    PDF »
Semaphorin signaling in cancer cells and in cells of the tumor microenvironment - two sides of a coin.
L. Capparuccia and L. Tamagnone (2009)
J. Cell Sci. 122, 1723-1736
   Abstract »    Full Text »    PDF »
Different Requirement for Rnd GTPases of R-Ras GAP Activity of Plexin-C1 and Plexin-D1.
K. Uesugi, I. Oinuma, H. Katoh, and M. Negishi (2009)
J. Biol. Chem. 284, 6743-6751
   Abstract »    Full Text »    PDF »
ABL2/ARG Tyrosine Kinase Mediates SEMA3F-induced RhoA Inactivation and Cytoskeleton Collapse in Human Glioma Cells.
A. Shimizu, A. Mammoto, J. E. Italiano Jr., E. Pravda, A. C. Dudley, D. E. Ingber, and M. Klagsbrun (2008)
J. Biol. Chem. 283, 27230-27238
   Abstract »    Full Text »    PDF »
Semaphorin-3B Is an Angiogenesis Inhibitor That Is Inactivated by Furin-Like Pro-Protein Convertases.
A. Varshavsky, O. Kessler, S. Abramovitch, B. Kigel, S. Zaffryar, G. Akiri, and G. Neufeld (2008)
Cancer Res. 68, 6922-6931
   Abstract »    Full Text »    PDF »
Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos.
A. Trindade, S. Ram Kumar, J. S. Scehnet, L. Lopes-da-Costa, J. Becker, W. Jiang, R. Liu, P. S. Gill, and A. Duarte (2008)
Blood 112, 1720-1729
   Abstract »    Full Text »    PDF »
Four-dimensional analysis of vascularization during primary development of an organ, the gonad.
D. Coveney, J. Cool, T. Oliver, and B. Capel (2008)
PNAS 105, 7212-7217
   Abstract »    Full Text »    PDF »
Besides adhesion: new perspectives of integrin functions in angiogenesis.
G. Serini, L. Napione, M. Arese, and F. Bussolino (2008)
Cardiovasc Res 78, 213-222
   Abstract »    Full Text »    PDF »
Neural guidance molecules, tip cells, and mechanical factors in vascular development.
F. le Noble, C. Klein, A. Tintu, A. Pries, and I. Buschmann (2008)
Cardiovasc Res 78, 232-241
   Abstract »    Full Text »    PDF »
Plexin-A4 negatively regulates T lymphocyte responses.
M. Yamamoto, K. Suzuki, T. Okuno, T. Ogata, N. Takegahara, H. Takamatsu, M. Mizui, M. Taniguchi, A. Chedotal, F. Suto, et al. (2008)
Int. Immunol. 20, 413-420
   Abstract »    Full Text »    PDF »
Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum.
P. Arlotta, B. J. Molyneaux, D. Jabaudon, Y. Yoshida, and J. D. Macklis (2008)
J. Neurosci. 28, 622-632
   Abstract »    Full Text »    PDF »
Semaphorin3D Regulates Axon Axon Interactions by Modulating Levels of L1 Cell Adhesion Molecule.
M. A. Wolman, A. M. Regnery, T. Becker, C. G. Becker, and M. C. Halloran (2007)
J. Neurosci. 27, 9653-9663
   Abstract »    Full Text »    PDF »
Site-directed Mutagenesis in the B-Neuropilin-2 Domain Selectively Enhances Its Affinity to VEGF165, but Not to Semaphorin 3F.
E. Geretti, A. Shimizu, P. Kurschat, and M. Klagsbrun (2007)
J. Biol. Chem. 282, 25698-25707
   Abstract »    Full Text »    PDF »
Semaphorin signaling facilitates cleft formation in the developing salivary gland.
L. Chung, T.-L. Yang, H.-R. Huang, S.-M. Hsu, H.-J. Cheng, and P.-H. Huang (2007)
Development 134, 2935-2945
   Abstract »    Full Text »    PDF »
Plexin-B2, But Not Plexin-B1, Critically Modulates Neuronal Migration and Patterning of the Developing Nervous System In Vivo.
S. Deng, A. Hirschberg, T. Worzfeld, J. Y. Penachioni, A. Korostylev, J. M. Swiercz, P. Vodrazka, O. Mauti, E. T. Stoeckli, L. Tamagnone, et al. (2007)
J. Neurosci. 27, 6333-6347
   Abstract »    Full Text »    PDF »
Selective requirements for NRP1 ligands during neurovascular patterning.
J. M. Vieira, Q. Schwarz, and C. Ruhrberg (2007)
Development 134, 1833-1843
   Abstract »    Full Text »    PDF »
Plexin-B2 Controls the Development of Cerebellar Granule Cells.
R. H. Friedel, G. Kerjan, H. Rayburn, U. Schuller, C. Sotelo, M. Tessier-Lavigne, and A. Chedotal (2007)
J. Neurosci. 27, 3921-3932
   Abstract »    Full Text »    PDF »
Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1.
T. Toyofuku, M. Yabuki, J. Kamei, M. Kamei, N. Makino, A. Kumanogoh, and M. Hori (2007)
EMBO J. 26, 1373-1384
   Abstract »    Full Text »    PDF »
Poor Outcome in Estrogen Receptor-Positive Breast Cancers Predicted by Loss of Plexin B1.
A. Rody, U. Holtrich, R. Gaetje, M. Gehrmann, K. Engels, G. von Minckwitz, S. Loibl, R. Diallo-Danebrock, E. Ruckhaberle, D. Metzler, et al. (2007)
Clin. Cancer Res. 13, 1115-1122
   Abstract »    Full Text »    PDF »
X-ray fluorescence microscopy reveals large-scale relocalization and extracellular translocation of cellular copper during angiogenesis.
L. Finney, S. Mandava, L. Ursos, W. Zhang, D. Rodi, S. Vogt, D. Legnini, J. Maser, F. Ikpatt, O. I. Olopade, et al. (2007)
PNAS 104, 2247-2252
   Abstract »    Full Text »    PDF »
Axon Pruning and Synaptic Development: How Are They per-Plexin?.
K. E. Waimey and H.-J. Cheng (2006)
Neuroscientist 12, 398-409
   Abstract »    PDF »
Drosophila Plexin B is a Sema-2a receptor required for axon guidance.
J. C. Ayoob, J. R. Terman, and A. L. Kolodkin (2006)
Development 133, 2125-2135
   Abstract »    Full Text »    PDF »
Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A.
M. Narazaki and G. Tosato (2006)
Blood 107, 3892-3901
   Abstract »    Full Text »    PDF »
Vascular endothelial-derived semaphorin 3 inhibits sympathetic axon growth.
D. H. Damon (2006)
Am J Physiol Heart Circ Physiol 290, H1220-H1225
   Abstract »    Full Text »    PDF »
Neuron Restrictive Silencer Factor NRSF/REST Is a Transcriptional Repressor of Neuropilin-1 and Diminishes the Ability of Semaphorin 3A to Inhibit Keratinocyte Migration.
P. Kurschat, D. Bielenberg, M. Rossignol-Tallandier, A. Stahl, and M. Klagsbrun (2006)
J. Biol. Chem. 281, 2721-2729
   Abstract »    Full Text »    PDF »
Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy?.
I. Roodink, J. Raats, B. van der Zwaag, K. Verrijp, B. Kusters, H. van Bokhoven, M. Linkels, R. M.W. de Waal, and W. P.J. Leenders (2005)
Cancer Res. 65, 8317-8323
   Abstract »    Full Text »    PDF »
Proteolytic Processing Converts the Repelling Signal Sema3E into an Inducer of Invasive Growth and Lung Metastasis.
C. Christensen, N. Ambartsumian, G. Gilestro, B. Thomsen, P. Comoglio, L. Tamagnone, P. Guldberg, and E. Lukanidin (2005)
Cancer Res. 65, 6167-6177
   Abstract »    Full Text »    PDF »
Class 3 Semaphorin Signaling: The End of a Dogma.
V. Potiron and J. Roche (2005)
Sci. STKE 2005, pe24
   Abstract »    Full Text »    PDF »
Plexin-A4 Mediates Axon-Repulsive Activities of Both Secreted and Transmembrane Semaphorins and Plays Roles in Nerve Fiber Guidance.
F. Suto, K. Ito, M. Uemura, M. Shimizu, Y. Shinkawa, M. Sanbo, T. Shinoda, M. Tsuboi, S. Takashima, T. Yagi, et al. (2005)
J. Neurosci. 25, 3628-3637
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882