Abstract
Semaphorins are extracellular signaling proteins that are essential for the development and maintenance of many organs and tissues. The more than 20-member semaphorin protein family includes secreted, transmembrane and cell surface-attached proteins with diverse structures, each characterized by a single cysteine-rich extracellular sema domain, the defining feature of the family. Early studies revealed that semaphorins function as axon guidance molecules, but it is now understood that semaphorins are key regulators of morphology and motility in many different cell types including those that make up the nervous, cardiovascular, immune, endocrine, hepatic, renal, reproductive, respiratory and musculoskeletal systems, as well as in cancer cells. Semaphorin signaling occurs predominantly through Plexin receptors and results in changes to the cytoskeletal and adhesive machinery that regulate cellular morphology. While much remains to be learned about the mechanisms underlying the effects of semaphorins, exciting work has begun to reveal how semaphorin signaling is fine-tuned through different receptor complexes and other mechanisms to achieve specific outcomes in various cellular contexts and physiological systems. These and future studies will lead to a more complete understanding of semaphorin-mediated development and to a greater understanding of how these proteins function in human disease.
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References
Yazdani U, Terman JR (2006) The semaphorins. Genome Biol 7:211
Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389–1399
Kolodkin AL, Matthes DJ, O’Connor TP et al (1992) Fasciclin IV: sequence, expression, and function during growth cone guidance in the grasshopper embryo. Neuron 9:831–845
Raper JA, Kapfhammer JP (1990) The enrichment of a neuronal growth cone collapsing activity from embryonic chick brain. Neuron 4:21–29
Luo Y, Raible D, Raper JA (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75:217–227
Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274:1123–1133
Semaphorin Nomenclature Committee (1999) Unified nomenclature for the semaphorins/collapsins. Cell 97:551–552
Browne K, Wang W, Liu RQ et al (2012) Transmembrane semaphorin5B is proteolytically processed into a repulsive neural guidance cue. J Neurochem 123:135–146
Elhabazi A, Delaire S, Bensussan A et al (2001) Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. J Immunol 166:4341–4347
Holmes S, Downs AM, Fosberry A et al (2002) Sema7A is a potent monocyte stimulator. Scand J Immunol 56:270–275
Gherardi E, Love CA, Esnouf RM et al (2004) The sema domain. Curr Opin Struct Biol 14:669–678
Hota PK, Buck M (2012) Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell Mol Life Sci 69:3765–3805
Takamatsu H, Kumanogoh A (2012) Diverse roles for semaphorin-plexin signaling in the immune system. Trends Immunol 33:127–135
Siebold C, Jones EY (2013) Structural insights into semaphorins and their receptors. Semin Cell Dev Biol 24:139–145
Antipenko A, Himanen JP, van Leyen K et al (2003) Structure of the semaphorin-3A receptor binding module. Neuron 39:589–598
Janssen BJ, Malinauskas T, Weir GA et al (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19:1293–1299
Janssen BJ, Robinson RA, Perez-Branguli F et al (2010) Structural basis of semaphorin-plexin signalling. Nature 467:1118–1122
Liu H, Juo ZS, Shim AH et al (2010) Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. Cell 142:749–761
Love CA, Harlos K, Mavaddat N et al (2003) The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol 10:843–848
Nogi T, Yasui N, Mihara E et al (2010) Structural basis for semaphorin signalling through the plexin receptor. Nature 467:1123–1127
Klostermann A, Lohrum M, Adams RH et al (1998) The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J Biol Chem 273:7326–7331
Koppel AM, Raper JA (1998) Collapsin-1 covalently dimerizes, and dimerization is necessary for collapsing activity. J Biol Chem 273:15708–15713
Perala N, Sariola H, Immonen T (2012) More than nervous: the emerging roles of plexins. Differentiation 83:77–91
Ohta K, Mizutani A, Kawakami A et al (1995) Plexin: a novel neuronal cell surface molecule that mediates cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Neuron 14:1189–1199
Comeau MR, Johnson R, DuBose RF et al (1998) A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR. Immunity 8:473–482
Chen H, Chedotal A, He Z et al (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19:547–559
He Z, Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90:739–751
Kolodkin AL, Levengood DV, Rowe EG et al (1997) Neuropilin is a semaphorin III receptor. Cell 90:753–762
Raimondi C, Ruhrberg C (2013) Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol 24:172–178
Gu C, Yoshida Y, Livet J et al (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268
Nakamura F, Tanaka M, Takahashi T et al (1998) Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Neuron 21:1093–1100
Renzi MJ, Feiner L, Koppel AM et al (1999) A dominant negative receptor for specific secreted semaphorins is generated by deleting an extracellular domain from neuropilin-1. J Neurosci 19:7870–7880
Tran TS, Rubio ME, Clem RL et al (2009) Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462:1065–1069
Sharma A, Verhaagen J, Harvey AR (2012) Receptor complexes for each of the Class 3 Semaphorins. Front Cell Neurosci 6:28
Kumanogoh A, Watanabe C, Lee I et al (2000) Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13:621–631
Kumanogoh A, Marukawa S, Suzuki K et al (2002) Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419:629–633
Pasterkamp RJ, Peschon JJ, Spriggs MK et al (2003) Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424:398–405
Cho JY, Chak K, Andreone BJ et al (2012) The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance. Genes Dev 26:2222–2235
De Wit J, De Winter F, Klooster J et al (2005) Semaphorin 3A displays a punctate distribution on the surface of neuronal cells and interacts with proteoglycans in the extracellular matrix. Mol Cell Neurosci 29:40–55
Kantor DB, Chivatakarn O, Peer KL et al (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975
Cagnoni G, Tamagnone L (2013) Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression. Oncogene 33:4795–4802
Franco M, Tamagnone L (2008) Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Rep 9:865–871
Bellon A, Luchino J, Haigh K et al (2010) VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 66:205–219
Toyofuku T, Zhang H, Kumanogoh A et al (2004) Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 18:435–447
Zhou Y, Gunput RA, Pasterkamp RJ (2008) Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 33:161–170
Jongbloets BC, Pasterkamp RJ (2014) Semaphorin signalling during development. Development 141:3292–3297
Casazza A, Fazzari P, Tamagnone L (2007) Semaphorin signals in cell adhesion and cell migration: functional role and molecular mechanisms. Adv Exp Med Biol 600:90–108
Hung RJ, Pak CW, Terman JR (2011) Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334:1710–1713
Kolodkin AL, Tessier-Lavigne M (2011) Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb Perspect Biol 3:a001727
Kruger RP, Aurandt J, Guan KL (2005) Semaphorins command cells to move. Nat Rev Mol Cell Biol 6:789–800
Pasterkamp RJ, Giger RJ (2009) Semaphorin function in neural plasticity and disease. Curr Opin Neurobiol 19:263–274
Fan J, Mansfield SG, Redmond T et al (1993) The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor. J Cell Biol 121:867–878
Hung RJ, Terman JR (2011) Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL-mediated actin filament disassembly. Cytoskeleton (Hoboken) 68:415–433
Puschel AW (2007) GTPases in semaphorin signaling. Adv Exp Med Biol 600:12–23
Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877
Wang Y, He H, Srivastava N et al (2012) Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal 5:ra6
Oinuma I, Ishikawa Y, Katoh H et al (2004) The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305:862–865
Yang T, Terman JR (2013) Regulating small G protein signaling to coordinate axon adhesion and repulsion. Small GTPases 4:34–41
Hall A, Lalli G (2010) Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol 2:a001818
Kinbara K, Goldfinger LE, Hansen M et al (2003) Ras GTPases: integrins’ friends or foes? Nat Rev Mol Cell Biol 4:767–776
Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635
Chardin P (2006) Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol 7:54–62
Negishi M, Oinuma I, Katoh H (2005) Plexins: axon guidance and signal transduction. Cell Mol Life Sci 62:1363–1371
Hung RJ, Yazdani U, Yoon J et al (2010) Mical links semaphorins to F-actin disassembly. Nature 463:823–827
Hung RJ, Spaeth CS, Yesilyurt HG et al (2013) SelR reverses Mical-mediated oxidation of actin to regulate F-actin dynamics. Nat Cell Biol 15:1445–1454
Lee BC, Peterfi Z, Hoffmann FW et al (2013) MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation. Mol Cell 51:397–404
Pasterkamp RJ (2005) R-Ras fills another GAP in semaphorin signalling. Trends Cell Biol 15:61–64
Schmidt EF, Strittmatter SM (2007) The CRMP family of proteins and their role in Sema3A signaling. Adv Exp Med Biol 600:1–11
Tojima T, Hines JH, Henley JR et al (2011) Second messengers and membrane trafficking direct and organize growth cone steering. Nat Rev Neurosci 12:191–203
Tojima T, Itofusa R, Kamiguchi H (2010) Asymmetric clathrin-mediated endocytosis drives repulsive growth cone guidance. Neuron 66:370–377
Wolman MA, Liu Y, Tawarayama H et al (2004) Repulsion and attraction of axons by semaphorin3D are mediated by different neuropilins in vivo. J Neurosci 24:8428–8435
Chauvet S, Cohen S, Yoshida Y et al (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822
Polleux F, Morrow T, Ghosh A (2000) Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404:567–573
Song H, Ming G, He Z et al (1998) Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281:1515–1518
Yang T, Terman JR (2012) 14-3-3epsilon couples protein kinase A to semaphorin signaling and silences plexin RasGAP-mediated axonal repulsion. Neuron 74:108–121
Haklai-Topper L, Mlechkovich G, Savariego D et al (2010) Cis interaction between Semaphorin6A and Plexin-A4 modulates the repulsive response to Sema6A. EMBO J 29:2635–2645
Sun LO, Jiang Z, Rivlin-Etzion M et al (2013) On and off retinal circuit assembly by divergent molecular mechanisms. Science 342:1241974
Suto F, Tsuboi M, Kamiya H et al (2007) Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53:535–547
Mizumoto K, Shen K (2013) Interaxonal interaction defines tiled presynaptic innervation in C. elegans. Neuron 77:655–666
Jeong S, Juhaszova K, Kolodkin AL (2012) The control of semaphorin-1a-mediated reverse signaling by opposing pebble and RhoGAPp190 functions in drosophila. Neuron 76:721–734
Sweeney LB, Chou YH, Wu Z et al (2011) Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting. Neuron 72:734–747
Law CO, Kirby RJ, Aghamohammadzadeh S et al (2008) The neural adhesion molecule TAG-1 modulates responses of sensory axons to diffusible guidance signals. Development 135:2361–2371
Dang P, Smythe E, Furley AJ (2012) TAG1 regulates the endocytic trafficking and signaling of the semaphorin3A receptor complex. J Neurosci 32:10370–10382
Carcea I, Ma’ayan A, Mesias R et al (2010) Flotillin-mediated endocytic events dictate cell type-specific responses to semaphorin 3A. J Neurosci 30:15317–15329
Tran TS, Kolodkin AL, Bharadwaj R (2007) Semaphorin regulation of cellular morphology. Annu Rev Cell Dev Biol 23:263–292
Yoshida Y (2012) Semaphorin signaling in vertebrate neural circuit assembly. Front Mol Neurosci 5:71
Ruhrberg C, Schwarz Q (2010) In the beginning: generating neural crest cell diversity. Cell Adhes Migr 4:622–630
Marin O, Rubenstein JL (2003) Cell migration in the forebrain. Annu Rev Neurosci 26:441–483
Marin O, Yaron A, Bagri A et al (2001) Sorting of striatal and cortical interneurons regulated by semaphorin–neuropilin interactions. Science 293:872–875
Chen G, Sima J, Jin M et al (2008) Semaphorin-3A guides radial migration of cortical neurons during development. Nat Neurosci 11:36–44
Kerjan G, Dolan J, Haumaitre C et al (2005) The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nat Neurosci 8:1516–1524
Renaud J, Kerjan G, Sumita I et al (2008) Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells. Nat Neurosci 11:440–449
Bron R, Vermeren M, Kokot N et al (2007) Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism. Neural Dev 2:21
Mauti O, Domanitskaya E, Andermatt I et al (2007) Semaphorin6A acts as a gate keeper between the central and the peripheral nervous system. Neural Dev 2:28
Vermeren M, Maro GS, Bron R et al (2003) Integrity of developing spinal motor columns is regulated by neural crest derivatives at motor exit points. Neuron 37:403–415
Wang F, Julien DP, Sagasti A (2013) Journey to the skin: somatosensory peripheral axon guidance and morphogenesis. Cell Adhes Migr 7:388–394
Zou Y, Stoeckli E, Chen H et al (2000) Squeezing axons out of the gray matter: a role for slit and semaphorin proteins from midline and ventral spinal cord. Cell 102:363–375
Kuwajima T, Yoshida Y, Takegahara N et al (2012) Optic chiasm presentation of Semaphorin6D in the context of Plexin-A1 and Nr-CAM promotes retinal axon midline crossing. Neuron 74:676–690
Faulkner RL, Low LK, Liu XB et al (2008) Dorsal turning of motor corticospinal axons at the pyramidal decussation requires plexin signaling. Neural Dev 3:21
Runker AE, Little GE, Suto F et al (2008) Semaphorin-6A controls guidance of corticospinal tract axons at multiple choice points. Neural Dev 3:34
Niquille M, Garel S, Mann F et al (2009) Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C. PLoS Biol 7:e1000230
Leighton PA, Mitchell KJ, Goodrich LV et al (2001) Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410:174–179
Winberg ML, Noordermeer JN, Tamagnone L et al (1998) Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95:903–916
Yu HH, Araj HH, Ralls SA et al (1998) The transmembrane Semaphorin Sema I is required in Drosophila for embryonic motor and CNS axon guidance. Neuron 20:207–220
Bashaw GJ (2007) Semaphorin directs axon traffic in the fly olfactory system. Neuron 53:157–159
Imai T (2012) Positional information in neural map development: lessons from the olfactory system. Develop Growth Differ 54:358–365
Nishiyama M, Togashi K, von Schimmelmann MJ et al (2011) Semaphorin 3A induces CaV2.3 channel-dependent conversion of axons to dendrites. Nat Cell Biol 13:676–685
Shelly M, Cancedda L, Lim BK et al (2011) Semaphorin3A regulates neuronal polarization by suppressing axon formation and promoting dendrite growth. Neuron 71:433–446
Yoshida Y, Han B, Mendelsohn M et al (2006) PlexinA1 signaling directs the segregation of proprioceptive sensory axons in the developing spinal cord. Neuron 52:775–788
Campbell DS, Regan AG, Lopez JS et al (2001) Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. J Neurosci 21:8538–8547
Liu Y, Berndt J, Su F et al (2004) Semaphorin3D guides retinal axons along the dorsoventral axis of the tectum. J Neurosci 24:310–318
Baier H (2013) Synaptic laminae in the visual system: molecular mechanisms forming layers of perception. Annu Rev Cell Dev Biol 29:385–416
Tawarayama H, Yoshida Y, Suto F et al (2010) Roles of semaphorin-6B and plexin-A2 in lamina-restricted projection of hippocampal mossy fibers. J Neurosci 30:7049–7060
Oh WJ, Gu C (2013) The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development. Semin Cell Dev Biol 24:156–162
Tillo M, Ruhrberg C, Mackenzie F (2012) Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity. Cell Adhes Migr 6:541–546
Vanderhaeghen P, Cheng HJ (2010) Guidance molecules in axon pruning and cell death. Cold Spring Harb Perspect Biol 2:a001859
Joo WJ, Sweeney LB, Liang L et al (2013) Linking cell fate, trajectory choice, and target selection: genetic analysis of Sema-2b in olfactory axon targeting. Neuron 78:673–686
Riccomagno MM, Hurtado A, Wang H et al (2012) The RacGAP beta2-Chimaerin selectively mediates axonal pruning in the hippocampus. Cell 149:1594–1606
Mann F, Chauvet S, Rougon G (2007) Semaphorins in development and adult brain: implication for neurological diseases. Prog Neurobiol 82:57–79
Yaron A, Zheng B (2007) Navigating their way to the clinic: emerging roles for axon guidance molecules in neurological disorders and injury. Dev Neurobiol 67:1216–1231
Lalani SR, Safiullah AM, Molinari LM et al (2004) SEMA3E mutation in a patient with CHARGE syndrome. J Med Genet 41:e94
Gant JC, Thibault O, Blalock EM et al (2009) Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy. Epilepsia 50:629–645
Yang J, Houk B, Shah J et al (2005) Genetic background regulates semaphorin gene expression and epileptogenesis in mouse brain after kainic acid status epilepticus. Neuroscience 131:853–869
Fujii T, Uchiyama H, Yamamoto N et al (2011) Possible association of the semaphorin 3D gene (SEMA3D) with schizophrenia. J Psychiatr Res 45:47–53
Mah S, Nelson MR, Delisi LE et al (2006) Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Mol Psychiatry 11:471–478
Runker AE, O’Tuathaigh C, Dunleavy M et al (2011) Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology. PLoS One 6:e26488
Wray NR, James MR, Mah SP et al (2007) Anxiety and comorbid measures associated with PLXNA2. Arch Gen Psychiatry 64:318–326
Rujescu D, Meisenzahl EM, Krejcova S et al (2007) Plexin B3 is genetically associated with verbal performance and white matter volume in human brain. Mol Psychiatry 12:190–194, 115
Good PF, Alapat D, Hsu A et al (2004) A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer’s disease. J Neurochem 91:716–736
Uchida Y, Ohshima T, Sasaki Y et al (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells 10:165–179
Clarimon J, Scholz S, Fung HC et al (2006) Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease. Am J Hum Genet 78:1082–1084, author reply 1092–1094
Maraganore DM, de Andrade M, Lesnick TG et al (2005) High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77:685–693
Van Battum EY, Brignani S, Pasterkamp RJ (2015) Axon guidance proteins in neurological disorders. Lancet Neurol 14:532–546
Kotter MR, Stadelmann C, Hartung HP (2011) Enhancing remyelination in disease--can we wrap it up? Brain 134:1882–1900
Fawcett JW, Schwab ME, Montani L et al (2012) Defeating inhibition of regeneration by scar and myelin components. Handb Clin Neurol 109:503–522
Giger RJ, Hollis ER 2nd, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2:a001867
Armendariz BG, Bribian A, Perez-Martinez E et al (2012) Expression of Semaphorin 4F in neurons and brain oligodendrocytes and the regulation of oligodendrocyte precursor migration in the optic nerve. Mol Cell Neurosci 49:54–67
Bernard F, Moreau-Fauvarque C, Heitz-Marchaland C et al (2012) Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination. Glia 60:1590–1604
Cohen RI (2005) Exploring oligodendrocyte guidance: ‘to boldly go where no cell has gone before’. Cell Mol Life Sci 62:505–510
Leslie JR, Imai F, Fukuhara K et al (2011) Ectopic myelinating oligodendrocytes in the dorsal spinal cord as a consequence of altered semaphorin 6D signaling inhibit synapse formation. Development 138:4085–4095
Xiang X, Zhang X, Huang QL (2012) Plexin A3 is involved in semaphorin 3F-mediated oligodendrocyte precursor cell migration. Neurosci Lett 530:127–132
Yamaguchi W, Tamai R, Kageura M et al (2012) Sema4D as an inhibitory regulator in oligodendrocyte development. Mol Cell Neurosci 49:290–299
Syed YA, Hand E, Mobius W et al (2011) Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci 31:3719–3728
Giacobini P, Prevot V (2013) Semaphorins in the development, homeostasis and disease of hormone systems. Semin Cell Dev Biol 24:190–198
Messina A, Giacobini P (2013) Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system. Front Endocrinol 4:133
Herbison AE (2006) Physiology of the gonadotropin-releasing hormone neuronal network. In: Knobil E, Neill JD (eds) Physiology of Reproduction, 3rd edn. Elsevier, New York, pp 1415–1482
Giacobini P, Messina A, Morello F et al (2008) Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex. J Cell Biol 183:555–566
Messina A, Ferraris N, Wray S et al (2011) Dysregulation of Semaphorin7A/beta1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility. Hum Mol Genet 20:4759–4774
Cariboni A, Hickok J, Rakic S et al (2007) Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci 27:2387–2395
Cariboni A, Davidson K, Rakic S et al (2011) Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Hum Mol Genet 20:336–344
Parkash J, Messina A, Langlet F et al (2015) Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence. Nat Commun 6:6385
Regev A, Goldman S, Shalev E (2007) Semaphorin-4D (Sema-4D), the Plexin-B1 ligand, is involved in mouse ovary follicular development. Reprod Biol Endocrinol 5:12
Dacquin R, Domenget C, Kumanogoh A et al (2011) Control of bone resorption by semaphorin 4D is dependent on ovarian function. PLoS One 6:e26627
Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200
Gelfand MV, Hong S, Gu C (2009) Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning. Trends Cell Biol 19:99–110
Adams RH, Eichmann A (2010) Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol 2:a001875
Tamagnone L, Mazzone M (2011) Semaphorin signals on the road of endothelial tip cells. Dev Cell 21:189–190
van der Zwaag B, Hellemons AJ, Leenders WP et al (2002) PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev Dyn 225:336–343
Behar O, Golden JA, Mashimo H et al (1996) Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 383:525–528
Feiner L, Webber AL, Brown CB et al (2001) Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128:3061–3070
Gitler AD, Lu MM, Epstein JA (2004) PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev Cell 7:107–116
Toyofuku T, Kikutani H (2007) Semaphorin signaling during cardiac development. Adv Exp Med Biol 600:109–117
Ieda M, Fukuda K (2009) New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles: the regulatory mechanisms of cardiac innervation and their critical roles in cardiac performance. J Pharmacol Sci 109:348–353
Bouvree K, Brunet I, Del Toro R et al (2012) Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation. Circ Res 111:437–445
Jurisic G, Maby-El Hajjami H, Karaman S et al (2012) An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ Res 111:426–436
Azzi S, Hebda JK, Gavard J (2013) Vascular permeability and drug delivery in cancers. Front Oncol 3:211
Treps L, Le Guelte A, Gavard J (2013) Emerging roles of Semaphorins in the regulation of epithelial and endothelial junctions. Tissue Barriers 1:e23272
Wannemacher KM, Wang L, Zhu L et al (2011) The role of semaphorins and their receptors in platelets: lessons learned from neuronal and immune synapses. Platelets 22:461–465
Chauvet S, Burk K, Mann F (2013) Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues. Cell Mol Life Sci 70:1685–1703
Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2:a006502
Bougeret C, Mansur IG, Dastot H et al (1992) Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation. J Immunol 148:318–323
Delaire S, Elhabazi A, Bensussan A et al (1998) CD100 is a leukocyte semaphorin. Cell Mol Life Sci 54:1265–1276
Kumanogoh A, Kikutani H (2013) Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nat Rev Immunol 13:802–814
Roney K, Holl E, Ting J (2013) Immune plexins and semaphorins: old proteins, new immune functions. Protein Cell 4:17–26
Suzuki K, Kumanogoh A, Kikutani H (2008) Semaphorins and their receptors in immune cell interactions. Nat Immunol 9:17–23
Mendes-da-Cruz DA, Stimamiglio MA, Munoz JJ et al (2012) Developing T-cell migration: role of semaphorins and ephrins. FASEB J 26:4390–4399
Garcia F, Lepelletier Y, Smaniotto S et al (2012) Inhibitory effect of semaphorin-3A, a known axon guidance molecule, in the human thymocyte migration induced by CXCL12. J Leukoc Biol 91:7–13
Lepelletier Y, Smaniotto S, Hadj-Slimane R et al (2007) Control of human thymocyte migration by Neuropilin-1/Semaphorin-3A-mediated interactions. Proc Natl Acad Sci U S A 104:5545–5550
Choi YI, Duke-Cohan JS, Ahmed WB et al (2008) PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity 29:888–898
Takamatsu H, Takegahara N, Nakagawa Y et al (2010) Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat Immunol 11:594–600
Kumanogoh A, Shikina T, Suzuki K et al (2005) Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22:305–316
Kumanogoh A, Suzuki K, Ch’ng E et al (2002) Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J Immunol 169:1175–1181
Nakatsuji Y, Okuno T, Moriya M et al (2012) Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple sclerosis. J Immunol 188:4858–4865
Okuno T, Nakatsuji Y, Moriya M et al (2010) Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 184:1499–1506
Shi W, Kumanogoh A, Watanabe C et al (2000) The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13:633–642
Takegahara N, Takamatsu H, Toyofuku T et al (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8:615–622
Nakagawa Y, Takamatsu H, Okuno T et al (2011) Identification of semaphorin 4B as a negative regulator of basophil-mediated immune responses. J Immunol 186:2881–2888
Kang S, Okuno T, Takegahara N et al (2012) Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via alphavbeta1 integrin. J Immunol 188:1108–1116
Suzuki K, Okuno T, Yamamoto M et al (2007) Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 446:680–684
Harre U, Schett G (2013) Bone research in 2012: the ups and downs of bone in health and rheumatic disease. Nat Rev Rheumatol 9:67–68
Kang S, Kumanogoh A (2013) Semaphorins in bone development, homeostasis, and disease. Semin Cell Dev Biol 24:163–171
Del Fattore A, Teti A, Rucci N (2012) Bone cells and the mechanisms of bone remodelling. Front Biosci (Elite Ed) 4:2302–2321
Nakahama K (2010) Cellular communications in bone homeostasis and repair. Cell Mol Life Sci 67:4001–4009
Hayashi M, Nakashima T, Taniguchi M et al (2012) Osteoprotection by semaphorin 3A. Nature 485:69–74
Fukuda T, Takeda S, Xu R et al (2013) Sema3A regulates bone-mass accrual through sensory innervations. Nature 497:490–493
Kaifu T, Nakahara J, Inui M et al (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332
Koga T, Inui M, Inoue K et al (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763
Negishi-Koga T, Shinohara M, Komatsu N et al (2011) Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 17:1473–1480
Hwang JY, Lee JY, Park MH et al (2006) Association of PLXNA2 polymorphisms with vertebral fracture risk and bone mineral density in postmenopausal Korean population. Osteoporos Int 17:1592–1601
Koh JM, Oh B, Lee JY et al (2006) Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women. J Hum Genet 51:112–117
Sutton AL, Zhang X, Dowd DR et al (2008) Semaphorin 3B is a 1,25-Dihydroxyvitamin D3-induced gene in osteoblasts that promotes osteoclastogenesis and induces osteopenia in mice. Mol Endocrinol 22:1370–1381
Michos O (2009) Kidney development: from ureteric bud formation to branching morphogenesis. Curr Opin Genet Dev 19:484–490
Reidy K, Tufro A (2011) Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk. Pediatr Nephrol 26:1407–1412
Tapia R, Guan F, Gershin I et al (2008) Semaphorin3a disrupts podocyte foot processes causing acute proteinuria. Kidney Int 73:733–740
Veron D, Reidy KJ, Bertuccio C et al (2010) Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 77:989–999
Kagoshima M, Ito T (2001) Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis. Genes Cells 6:559–571
Roche J, Boldog F, Robinson M et al (1996) Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 12:1289–1297
Sekido Y, Bader S, Latif F et al (1996) Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A 93:4120–4125
Xiang RH, Hensel CH, Garcia DK et al (1996) Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics 32:39–48
Potiron VA, Roche J, Drabkin HA (2009) Semaphorins and their receptors in lung cancer. Cancer Lett 273:1–14
Gu C, Giraudo E (2013) The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res 319:1306–1316
Tamagnone L (2012) Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 22:145–152
Neufeld G, Sabag AD, Rabinovicz N et al (2012) Semaphorins in angiogenesis and tumor progression. Cold Spring Harb Perspect Med 2:a006718
Thirant C, Gavard J, Junier MP et al (2013) Critical multiple angiogenic factors secreted by glioblastoma stem-like cells underline the need for combinatorial anti-angiogenic therapeutic strategies. Proteomics Clin Appl 7:79–90
Bachelder RE, Lipscomb EA, Lin X et al (2003) Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63:5230–5233
Pan H, Bachelder RE (2010) Autocrine Semaphorin3A stimulates eukaryotic initiation factor 4E-dependent RhoA translation in breast tumor cells. Exp Cell Res 316:2825–2832
Herman JG, Meadows GG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30:1231–1238
Tomizawa Y, Sekido Y, Kondo M et al (2001) Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A 98:13954–13959
Xiang R, Davalos AR, Hensel CH et al (2002) Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res 62:2637–2643
Catalano A, Lazzarini R, Di Nuzzo S et al (2009) The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells. Cancer Res 69:1485–1493
Basile JR, Barac A, Zhu T et al (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64:5212–5224
Basile JR, Castilho RM, Williams VP et al (2006) Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A 103:9017–9022
Sierra JR, Corso S, Caione L et al (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685
Bielenberg DR, Hida Y, Shimizu A et al (2004) Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 114:1260–1271
Maione F, Molla F, Meda C et al (2009) Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119:3356–3372
Squadrito ML, De Palma M (2011) Macrophage regulation of tumor angiogenesis: implications for cancer therapy. Mol Asp Med 32:123–145
Barberis D, Casazza A, Sordella R et al (2005) p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci 118:4689–4700
Sun T, Krishnan R, Swiercz JM (2012) Grb2 mediates semaphorin-4D-dependent RhoA inactivation. J Cell Sci 125:3557–3567
Swiercz JM, Kuner R, Behrens J et al (2002) Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35:51–63
Swiercz JM, Kuner R, Offermanns S (2004) Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 165:869–880
Swiercz JM, Worzfeld T, Offermanns S (2008) ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem 283:1893–1901
Chak K, Kolodkin AL (2014) Function of the Drosophila receptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance. Development 141:136–147
Nagai H, Sugito N, Matsubara H et al (2007) CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. Oncogene 26:4025–4031
Acknowledgements
We thank Jeroen Pasterkamp for helpful comments on the manuscript. This work was supported by NIH (NS073968 and MH085923) and Welch Foundation (I-1749) grants to J.R.T.
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Alto, L.T., Terman, J.R. (2017). Semaphorins and their Signaling Mechanisms. In: Terman, J. (eds) Semaphorin Signaling. Methods in Molecular Biology, vol 1493. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6448-2_1
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