The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Yoshio Goshima - One of the best experts on this subject based on the ideXlab platform.
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regulation of dendritic development by Semaphorin 3A through novel intracellular remote signaling
Cell Adhesion & Migration, 2016Co-Authors: Yoshio Goshima, Fumio Nakamura, Naoya Yamashita, Yukio SasakiAbstract:Numerous cell adhesion molecules, extracellular matrix proteins and axon guidance molecules participate in neuronal network formation through local effects at axo-dendritic, axo-axonic or dendro-dendritic contact sites. In contrast, neurotrophins and their receptors play crucial roles in neural wiring by sending retrograde signals to remote cell bodies. Semaphorin 3A (Sema3A), a prototype of secreted type 3 Semaphorins, is implicated in axon repulsion, dendritic branching and synapse formation via binding protein neuropilin-1 (NRP1) and the signal transducing protein PlexinAs (PlexAs) complex. This review focuses on Sema3A retrograde signaling that regulates dendritic localization of AMPA-type glutamate receptor GluA2 and dendritic patterning. This signaling is elicited by activation of NRP1 in growth cones and is propagated to cell bodies by dynein-dependent retrograde axonal transport of PlexAs. It also requires interaction between PlexAs and a high-affinity receptor for nerve growth factor, toropomyosin receptor kinase A. We propose a control mechanism by which retrograde Sema3A signaling regulates the glutamate receptor localization through trafficking of cis-interacting PlexAs with GluA2 along dendrites; this remote signaling may be an alternative mechanism to local adhesive contacts for neural network formation.
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trka mediates retrograde Semaphorin 3A signaling through plexin a4 to regulate dendritic branching
Journal of Cell Science, 2016Co-Authors: Naoya Yamashita, Masayuki Yamane, Fumikazu Suto, Yoshio GoshimaAbstract:Semaphorin 3A (Sema3A), a secretory Semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of the PlexA4-TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)-Akt signal, a downstream signaling pathway of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning.
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Semaphorin 3A controls allergic and inflammatory responses in experimental allergic conjunctivitis
International Journal of Ophthalmology, 2015Co-Authors: Junmi Tanaka, Yoshio Goshima, Hideo Tanaka, Nobuhisa Mizuki, Eiichi Nomura, Norihiko Ito, Naoko Nomura, Masayuki Yamane, Tomonobu Hida, Hiroshi HatanoAbstract:AIM To assess the efficacy of topical Semaphorin-3A (SEMA3A) in the treatment of allergic conjunctivitis.
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plexin a4 dependent retrograde Semaphorin 3A signalling regulates the dendritic localization of glua2 containing ampa receptors
Nature Communications, 2014Co-Authors: Naoya Yamashita, Masahiko Taniguchi, Yukio Sasaki, Fumio Nakamura, Tomonobu Hida, Hiroshi Usui, Sandy Chen, Fumikazu Suto, Kohtaro Takei, Yoshio GoshimaAbstract:Semaphorin 3A is a guidance factor that is implicated in axonal and dendritic development. Here, Yamashita et al. show that Semaphorin 3A retrograde signalling via plexin A and dynein drives the localization of AMPA receptors to the dendrites where they are crucial for proper dendritic development.
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decreased expression of Semaphorin 3A a neurite collapsing factor is associated with itch in psoriatic skin
Acta Dermato-venereologica, 2012Co-Authors: Kenzen Kou, Yoshio Goshima, Fumio Nakamura, Michiko Aihara, Huichin Chen, Katsuya Seto, Junko Komoriyamaguchi, Takeshi Kambara, Yoji Nagashima, Zenro IkezawaAbstract:Pruritus is a common symptom of psoriasis, which affects quality of life. This symptom accompanies the hyper-innervation of sensory C-fibres in psoriatic lesions. Two extracellular molecules, nerve growth factor (NGF) and Semaphorin-3A, regulate C-fibre extension. In this study, the expression levels of these 2 molecules in biopsy specimens from psoriatic and healthy skin were quantified by immunohistochemistry and quantitative reverse-transcription PCR. Semaphorin-3A expression was lower in the psoriatic samples compared with the healthy samples, whereas NGF was higher. C-fibre innervation in the epidermis was also increased in psoriatic skin. Semaphorin-3A mRNA expression was negatively correlated with itch intensity and severity of psoriasis. We propose that decreased Semaphorin-3A and increased NGF expression levels may trigger the outgrowth of C-fibres, leading to pruritus.
Andreas W. Püschel - One of the best experts on this subject based on the ideXlab platform.
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structure of the Semaphorin 3A receptor binding module
Neuron, 2003Co-Authors: Alexander Antipenko, Andreas W. Püschel, Juhapekka Himanen, Klaus Van Leyen, Vincenzo Nardidei, Jacob Lesniak, William A Barton, Kanagalaghatta R Rajashankar, Claudia Hoemme, Dimitar B NikolovAbstract:Abstract The Semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. Their distinctive feature is a conserved 500 amino acid Semaphorin domain, a ligand-receptor interaction module also present in plexins and scatter-factor receptors. We report the crystal structure of a secreted 65 kDa form of Semaphorin-3A (Sema3A), containing the full Semaphorin domain. Unexpectedly, the Semaphorin fold is a variation of the β propeller topology. Analysis of the Sema3A structure and structure-based mutagenesis data identify the neuropilin binding site and suggest a potential plexin interaction site. Based on the structure, we present a model for the initiation of Semaphorin signaling and discuss potential similarities with the signaling mechanisms of other β propeller cell surface receptors, such as integrins and the LDL receptor.
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Antagonistic Effects of Rnd1 and RhoD GTPases Regulate Receptor Activity in Semaphorin 3A-Induced Cytoskeletal Collapse
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002Co-Authors: Silvio M. Zanata, Iiris Hovatta, Beate Rohm, Andreas W. PüschelAbstract:The Semaphorins are a large protein family that is involved in the patterning of neuronal connections in the developing nervous system of both vertebrates and invertebrates. The chemorepulsive axon guidance signal Semaphorin 3A (Sema3A) induces the depolymerization of actin filaments and the collapse of sensory growth cones by activating a receptor complex that contains a plexin as the signal-transducing subunit. Here we show that, of a large number of GTPases tested, only Rnd1 and RhoD bind the cytoplasmic domain of Plexin-A1. Recruitment of active Rnd1 is sufficient to trigger signaling by Plexin-A1, even in the absence of Sema3A, and initiates cytoskeletal collapse by activating its cytoplasmic domain. RhoD, in contrast, blocks Plexin-A1 activation by Rnd1 and repulsion of sympathetic axons by Sema3A. Thus, the antagonism of two GTPases regulates the activity of the Sema3A receptor, and activation by Rnd1 appears to be an essential step in signaling by Plexin-A1.
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Semaphorin 3A vascular endothelial growth factor 165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor
The Journal of Neuroscience, 2001Co-Authors: Dominique Bagnard, Andreas W. Püschel, Marion Lohrum, Jurgen Bolz, Catherine Vaillant, Sengthuon Khuth, Nathalie Dufay, M F Belin, Nicole ThomassetAbstract:The dynamic and coordinated interaction between cells and their microenvironment controls cell migration, proliferation, and apoptosis, mediated by different cell surface molecules. We have studied the response of a neuroectodermal progenitor cell line, Dev, to a guidance molecule, Semaphorin 3A (Sema3A), described previously as a repellent-collapsing signal for axons, and we have shown that Sema3A acts as a repellent guidance cue for migrating progenitor cells and, on prolonged application, induces apoptosis. Both repulsion and induction of cell death are mediated by neuropilin-1, the ligand-binding component of the Sema3A receptor. The vascular endothelial growth factor, VEGF165, antagonizes Sema3A-induced apoptosis and promotes cell survival, migration, and proliferation. Surprisingly, repulsion by Sema3A also depends on expression of VEGFR1, a VEGF165 receptor, expressed in Dev cells. Moreover, we found that these repulsive effects of Sema3A require tyrosine kinase activity, which can be attributed to VEGFR1. These results indicate that the balance between guidance molecules and angiogenic factors can modulate the migration, apoptosis (or survival), and proliferation of neural progenitor cells through shared receptors.
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the Semaphorin 3A receptor may directly regulate the activity of small gtpases
FEBS Letters, 2000Co-Authors: Beate Rohm, Iiris Hovatta, Belquis Rahim, Bedriska Kleiber, Andreas W. PüschelAbstract:The axon guidance signal Semaphorin 3A induces the rapid collapse of growth cones by activating a receptor complex that contains neuropilin-1 as the ligand-binding and a plexin as the signal-transducing subunit. Here we show that plexins bind Rho-like GTPases and may directly regulate their activity. The cytoplasmic domain of plexins shows sequence similarity to GTPase activating proteins (GAPs) and mutation of two arginines that correspond to the catalytic residues of Ras GAPs inactivates plexin-A1. Our data suggest that plexins may be integral membrane proteins with an intrinsic GAP activity that is essential for their ability to induce growth cone collapse.
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Semaphorin 3A is required for guidance of olfactory axons in mice
The Journal of Neuroscience, 2000Co-Authors: Gerald A Schwarting, Christine Kostek, Naira Ahmad, Christian Dibble, Laurent Pays, Andreas W. PüschelAbstract:Semaphorin 3A (Sema3A) is a membrane-associated secreted protein that has chemorepulsive properties for neuropilin-1 (npn-1)- expressing axons. Although mice lacking the Sema3A protein display skeletal abnormalities and heart defects, most axonal projections in the CNS develop normally. We show here that Sema3A is expressed in the lamina propria surrounding the olfactory epithelium (OE) and by ensheathing cells in the nerve layer of the ventral olfactory bulb (OB) throughout development. Subsets of sensory neurons expressing npn-1 are distributed throughout the OE and extend fibers to the developing OB. In wild-type mice, npn-1-positive (npn-1(+)) axons extend to lateral targets in the rostral OB and medial targets in the caudal OB, avoiding regions expressing Sema3A. In Sema3A homozygous mutant mice, many npn-1(+) axons are misrouted into and through the ventral nerve layer, beginning as early as embryonic day 13 and continuing at least until birth. At postnatal day 0, npn-1(+) glomeruli are atypically located in the ventral OB of Sema3A(-/-) mice, indicating that aberrant axon trajectories are not corrected during development and that connections are made in inappropriate target regions. In addition, subsets of OCAM(+) axons that normally project to the ventrolateral OB and some lactosamine-containing glycan(+) axons that normally target the ventral OB are also misrouted in Sema3A mutants. These observations indicate that Sema3A expression by ensheathing cells plays an important role in guiding olfactory axons into specific compartments of the OB.
Yukio Sasaki - One of the best experts on this subject based on the ideXlab platform.
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regulation of dendritic development by Semaphorin 3A through novel intracellular remote signaling
Cell Adhesion & Migration, 2016Co-Authors: Yoshio Goshima, Fumio Nakamura, Naoya Yamashita, Yukio SasakiAbstract:Numerous cell adhesion molecules, extracellular matrix proteins and axon guidance molecules participate in neuronal network formation through local effects at axo-dendritic, axo-axonic or dendro-dendritic contact sites. In contrast, neurotrophins and their receptors play crucial roles in neural wiring by sending retrograde signals to remote cell bodies. Semaphorin 3A (Sema3A), a prototype of secreted type 3 Semaphorins, is implicated in axon repulsion, dendritic branching and synapse formation via binding protein neuropilin-1 (NRP1) and the signal transducing protein PlexinAs (PlexAs) complex. This review focuses on Sema3A retrograde signaling that regulates dendritic localization of AMPA-type glutamate receptor GluA2 and dendritic patterning. This signaling is elicited by activation of NRP1 in growth cones and is propagated to cell bodies by dynein-dependent retrograde axonal transport of PlexAs. It also requires interaction between PlexAs and a high-affinity receptor for nerve growth factor, toropomyosin receptor kinase A. We propose a control mechanism by which retrograde Sema3A signaling regulates the glutamate receptor localization through trafficking of cis-interacting PlexAs with GluA2 along dendrites; this remote signaling may be an alternative mechanism to local adhesive contacts for neural network formation.
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plexin a4 dependent retrograde Semaphorin 3A signalling regulates the dendritic localization of glua2 containing ampa receptors
Nature Communications, 2014Co-Authors: Naoya Yamashita, Masahiko Taniguchi, Yukio Sasaki, Fumio Nakamura, Tomonobu Hida, Hiroshi Usui, Sandy Chen, Fumikazu Suto, Kohtaro Takei, Yoshio GoshimaAbstract:Semaphorin 3A is a guidance factor that is implicated in axonal and dendritic development. Here, Yamashita et al. show that Semaphorin 3A retrograde signalling via plexin A and dynein drives the localization of AMPA receptors to the dendrites where they are crucial for proper dendritic development.
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fyn and cdk5 mediate Semaphorin 3A signaling which is involved in regulation of dendrite orientation in cerebral cortex
Neuron, 2002Co-Authors: Yukio Sasaki, Masahiko Taniguchi, Yutaka Uchida, Takeshi Yagi, Toshio Ohshima, Chi Cheng, Oumi Nakajima, Takashi Nakayama, Reiji KishidaAbstract:Semaphorin-3A (Sema3A), a member of class 3 Semaphorins, regulates axon and dendrite guidance in the nervous system. How Sema3A and its receptors plexin-As and neuropilins regulate neuronal guidance is unknown. We observed that in fyn- and cdk5-deficient mice, Sema3A-induced growth cone collapse responses were attenuated compared to their heterologous controls. Cdk5 is associated with plexin-A2 through the active state of Fyn. Sema3A promotes Cdk5 activity through phosphorylation of Tyr15, a phosphorylation site with Fyn. A Cdk5 mutant (Tyr15 to Ala) shows a dominant-negative effect on the Sema3A-induced collapse response. The sema3A gene shows strong interaction with fyn for apical dendrite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regulated by Sema3A.
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Phosphorylation of cofilin by LIM-kinase is necessary for Semaphorin 3A-induced growth cone collapse
Nature Neuroscience, 2001Co-Authors: Hiroyuki Aizawa, Kensaku Mizuno, Yukio Sasaki, Shuji Wakatsuki, Ai Ishii, Kenji Moriyama, Kazumasa Ohashi, Yoko Sekine-aizawa, Atsuko Sehara-fujisawa, Yoshio GoshimaAbstract:Semaphorin 3A is a chemorepulsive axonal guidance molecule that depolymerizes the actin cytoskeleton and collapses growth cones of dorsal root ganglia neurons. Here we investigate the role of LIM-kinase 1, which phosphorylates an actin-depolymerizing protein, cofilin, in Semaphorin 3A-induced growth cone collapse. Semaphorin 3A induced phosphorylation and dephosphorylation of cofilin at growth cones sequentially. A synthetic cell-permeable peptide containing a cofilin phosphorylation site inhibited LIM-kinase in vitro and in vivo , and essentially suppressed Semaphorin 3A-induced growth cone collapse. A dominant-negative LIM kinase, which could not be activated by PAK or ROCK, suppressed the collapsing activity of Semaphorin 3A. Phosphorylation of cofilin by LIM-kinase may be a critical signaling event in growth cone collapse by Semaphorin 3A.
Naoya Yamashita - One of the best experts on this subject based on the ideXlab platform.
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regulation of dendritic development by Semaphorin 3A through novel intracellular remote signaling
Cell Adhesion & Migration, 2016Co-Authors: Yoshio Goshima, Fumio Nakamura, Naoya Yamashita, Yukio SasakiAbstract:Numerous cell adhesion molecules, extracellular matrix proteins and axon guidance molecules participate in neuronal network formation through local effects at axo-dendritic, axo-axonic or dendro-dendritic contact sites. In contrast, neurotrophins and their receptors play crucial roles in neural wiring by sending retrograde signals to remote cell bodies. Semaphorin 3A (Sema3A), a prototype of secreted type 3 Semaphorins, is implicated in axon repulsion, dendritic branching and synapse formation via binding protein neuropilin-1 (NRP1) and the signal transducing protein PlexinAs (PlexAs) complex. This review focuses on Sema3A retrograde signaling that regulates dendritic localization of AMPA-type glutamate receptor GluA2 and dendritic patterning. This signaling is elicited by activation of NRP1 in growth cones and is propagated to cell bodies by dynein-dependent retrograde axonal transport of PlexAs. It also requires interaction between PlexAs and a high-affinity receptor for nerve growth factor, toropomyosin receptor kinase A. We propose a control mechanism by which retrograde Sema3A signaling regulates the glutamate receptor localization through trafficking of cis-interacting PlexAs with GluA2 along dendrites; this remote signaling may be an alternative mechanism to local adhesive contacts for neural network formation.
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trka mediates retrograde Semaphorin 3A signaling through plexin a4 to regulate dendritic branching
Journal of Cell Science, 2016Co-Authors: Naoya Yamashita, Masayuki Yamane, Fumikazu Suto, Yoshio GoshimaAbstract:Semaphorin 3A (Sema3A), a secretory Semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of the PlexA4-TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)-Akt signal, a downstream signaling pathway of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning.
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anti Semaphorin 3A neutralization monoclonal antibody prevents sepsis development in lipopolysaccharide treated mice
International Immunology, 2015Co-Authors: Naoya Yamashita, Aoi Jitsukitakahashi, Miyuki Ogawara, Wataru Ohkubo, Tomomi Araki, Chie Hotta, Tomohiko Tamura, Shuichi Hashimoto, Takashi Yabuki, Toru TsujiAbstract:Semaphorin 3A (Sema3A), originally identified as a potent growth cone collapsing factor in developing sensory neurons, is now recognized as a key player in immune, cardiovascular, bone metabolism and neurological systems. Here we established an anti-Sema3A monoclonal antibody that neutralizes the effects of Sema3A both in vitro and in vivo. The anti-Sema3A neutralization chick IgM antibodies were screened by combining an autonomously diversifying library selection system and an in vitro growth cone collapse assay. We further developed function-blocking chick-mouse chimeric and humanized anti-Sema3A antibodies. We found that our anti-Sema3A antibodies were effective for improving the survival rate in lipopolysaccharide-induced sepsis in mice. Our antibody is a potential therapeutic agent that may prevent the onset of or alleviate symptoms of human diseases associated with Sema3A.
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plexin a4 dependent retrograde Semaphorin 3A signalling regulates the dendritic localization of glua2 containing ampa receptors
Nature Communications, 2014Co-Authors: Naoya Yamashita, Masahiko Taniguchi, Yukio Sasaki, Fumio Nakamura, Tomonobu Hida, Hiroshi Usui, Sandy Chen, Fumikazu Suto, Kohtaro Takei, Yoshio GoshimaAbstract:Semaphorin 3A is a guidance factor that is implicated in axonal and dendritic development. Here, Yamashita et al. show that Semaphorin 3A retrograde signalling via plexin A and dynein drives the localization of AMPA receptors to the dendrites where they are crucial for proper dendritic development.
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Semaphorin 3A induces cav2 3 channel dependent conversion of axons to dendrites
Nature Cell Biology, 2011Co-Authors: Makoto Nishiyama, Yoshio Goshima, Naoya Yamashita, Kazunobu Togashi, Melanie Von Schimmelmann, Chaeseok Lim, Shinichi Maeda, Shin Ishii, Kyonsoo HongAbstract:Polarized neurites (axons and dendrites) form the functional circuitry of the nervous system. Secreted guidance cues often control the polarity of neuron migration and neurite outgrowth by regulating ion channels. Here, we show that secreted Semaphorin 3A (Sema3A) induces the neurite identity of Xenopus spinal commissural interneurons (xSCINs) by activating Ca(V)2.3 channels (Ca(V)2.3). Sema3A treatment converted the identity of axons of cultured xSCINs to that of dendrites by recruiting functional Ca(V)2.3. Inhibition of Sema3A signalling prevented both the expression of Ca(V)2.3 and acquisition of the dendrite identity, and inhibition of Ca(V)2.3 function resulted in multiple axon-like neurites of xSCINs in the spinal cord. Furthermore, Sema3A-triggered cGMP production and PKG activity induced, respectively, the expression of functional Ca(V)2.3 and the dendrite identity. These results reveal a mechanism by which a guidance cue controls the identity of neurites during nervous system development.
Jacques Young - One of the best experts on this subject based on the ideXlab platform.
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sema3A deletion in a family with kallmann syndrome validates the role of Semaphorin 3A in human puberty and olfactory system development
Human Reproduction, 2012Co-Authors: Jacques Young, Corinne Metay, Jerome Bouligand, Bassim Tou, Bruno Francou, Luigi MaioneAbstract:background: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach. methods: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. results: One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus’ family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for Semaphorin 3A, a protein that interacts with neuropilins. Mice lacking Semaphorin 3A expression have been showed to have a Kallmann-like phenotype. conclusions: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of Semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.
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sema3A deletion in a family with kallmann syndrome validates the role of Semaphorin 3A in human puberty and olfactory system development
Human Reproduction, 2012Co-Authors: Jacques Young, Corinne Metay, Jerome Bouligand, Bruno Francou, Luigi Maione, Lucie Tosca, Julie Sarfati, Frederic Brioude, Blandine Esteva, Audrey BriandsuleauAbstract:BACKGROUND: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach. METHODS: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. RESULTS: One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus' family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for Semaphorin 3A, a protein that interacts with neuropilins. Mice lacking Semaphorin 3A expression have been showed to have a Kallmann-like phenotype. CONCLUSIONS: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of Semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.
