Gene Deletion Mutants Reveal a Role for Semaphorin Receptors of the Plexin-B Family in Mechanisms Underlying Corticogenesis

Hirschberg, Alexandra; Deng, Suhua; Korostylev, Alexander; Páldy, Eszter; Costa, Marcos Romualdo; Worzfeld, Thomas; Vodrazka, Peter; Wizenmann, Andrea; Götz, Magdalena; Offermanns, Stefan; Kuner, Rohini

doi:10.1128/mcb.01458-09

Cited by 42 publications

(34 citation statements)

References 46 publications

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“…Plxnb2 knockout mice (plxnb2 −/− ) display neural tube closure defects, which result in exencephaly and perinatal lethality (23,24). A small proportion of mice (∼5%) bypasses this neural tube closure phenotype and demonstrates abnormalities in cerebellar granule cell migration and defects in corticogenesis and migration of neuroblasts in the subventricular zone (23)(24)(25)(26). In our effort to understand which signaling functions of Plexin-B2 are relevant in vivo, we first generated BAC transgenic mice that express triple-myc-tagged wild-type Plexin-B2 (BAC B2WT).…”

Section: Resultsmentioning

confidence: 99%

“…Our data indicate that Plexin-B2-mediated RhoA activation is dispensable for development of the neocortex. Of note, the semaphorin ligand for Plexin-B2 in the embryonic cortex, Sema4D, also binds to the close Plexin-B2 homolog, Plexin-B1, with high affinity (1,25). Although Plexin-B1 is strongly expressed in the developing neocortex, the nervous system of Plexin-B1-deficient mice develops normally (23,41).…”

Section: Discussionmentioning

confidence: 99%

“…During development of the nervous system, Plexin-B2 is strongly expressed in the telencephalic ventricular and subventricular zone, as well as in the neuroepithelium of the medial and lateral ganglionic eminences, and mice lacking Plexin-B2 that bypass the neural tube closure defect display severe abnormalities in corticogenesis, including abnormal cortical layering and defective migration and differentiation of several subtypes of cortical neurons (25,41). The small GTPase RhoA plays a key role in the development of the nervous system by regulating a multitude of cellular functions, including cell migration, polarity, and survival (42,43), and regulation of RhoA activity is required for corticogenesis (44,45).…”

Section: Plexin-b2-mediated Rhoa Activation Is Dispensable For Neocormentioning

confidence: 99%

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Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian plexins constitute a family of transmembrane receptors for semaphorins and represent critical regulators of various processes during development of the nervous, cardiovascular, skeletal, and renal system. In vitro studies have shown that plexins exert their effects via an intracellular R-Ras/M-Ras GTPase-activating protein (GAP) domain or by activation of RhoA through interaction with Rho guanine nucleotide exchange factor proteins. However, which of these signaling pathways are relevant for plexin functions in vivo is largely unknown. Using an allelic series of transgenic mice, we show that the GAP domain of plexins constitutes their key signaling module during development. Mice in which endogenous Plexin-B2 or Plexin-D1 is replaced by transgenic versions harboring mutations in the GAP domain recapitulate the phenotypes of the respective null mutants in the developing nervous, vascular, and skeletal system. We further provide genetic evidence that, unexpectedly, the GAP domain-mediated developmental functions of plexins are not brought about via R-Ras and M-Ras inactivation. In contrast to the GAP domain mutants, Plexin-B2 transgenic mice defective in Rho guanine nucleotide exchange factor binding are viable and fertile but exhibit abnormal development of the liver vasculature. Our genetic analyses uncover the in vivo contextdependence and functional specificity of individual plexin-mediated signaling pathways during development.neural tube | cerebellum | outflow tract P lexins constitute a family of transmembrane proteins that serve as receptors for semaphorins (1). They function as key regulators of a multitude of developmental processes, including axon guidance, pattern and synapse formation in the nervous system (2), vasculogenesis and angiogenesis (3, 4), and morphogenesis of the heart, kidney, and skeletal system (5). In the adult organism, plexins play crucial roles in the physiology and pathophysiology of the immune and cardiovascular system, as well as in bone homeostasis and in cancer (6-9). Nine plexins have been identified in the mammalian system, which are grouped into four subfamilies, A-D, according to sequence homologies.The activation of plexins by their semaphorin ligands triggers several intracellular signaling cascades, most of which modulate the activity of small GTPases (10). The intracellular domain of all plexins shares homology with GTPase-activating proteins (GAPs) and confers the deactivation of R-Ras, M-Ras, and Rap1 (11-17). The GAP activity toward R-Ras and M-Ras, but not toward Rap1, requires binding of Rnd GTPases to the plexin receptor (11,12,15,16). Plexins of the B-subfamily differ from all other plexins in that they carry a C-terminal PDZ domain interaction motif that mediates a stable interaction with the Rho guanine nucleotide exchange factor (RhoGEF) proteins . Activation of B-plexins by semaphorin ligands results in activation of the RhoGEF proteins and subsequent activation of . This process and the GAP function of B-plexins are independent of each other, becau...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Plexin-b2-mediated Rhoa Activation Is Dispensable For Neocormentioning

confidence: 99%

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Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…3,[6][7][8] Subsequent studies have identified roles for Sema4D in axon guidance, [9][10][11][12] angiogenesis, [13][14][15][16][17] and tumor progression [18][19][20] and showed that some of these effects are mediated by the high-affinity receptor plexin-B1 20 and the related lower-affinity receptor plexin-B2. 21,22 In previously published studies, we have shown that Sema4D is expressed by platelets and that it participates in the hemostatic response to injury by reinforcing collagen-initiated platelet activation in a contact-dependent manner. 23,24 Deletion of Sema4D protects mice against the development of atherosclerosis by attenuating platelet hyperactivity in the setting of hyperlipidemia 25 and reducing intimal neovascularization, 26 which suggests that platelet Sema4D has an impact on the vessel wall as well as on platelets.…”

Section: Introductionmentioning

confidence: 99%

Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets

Mou

Zeng

Qiang

et al. 2013

Blood

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• This study identifies a calmodulin-binding sequence in Sema4D and shows that calmodulin binds to Sema4D in resting platelets.• Dissociation of the Sema4D:calmodulin complex is sufficient to trigger Sema4D cleavage and shedding of the extracellular domain.Semaphorin 4D (Sema4D) is a transmembrane protein that supports contact-dependent amplification of platelet activation by collagen before being gradually cleaved by the metalloprotease ADAM17, as we have previously shown. Cleavage releases a soluble 120-kDa exodomain fragment for which receptors exist on platelets and endothelial cells. Here we have examined the mechanism that regulates Sema4D exodomain cleavage. The results show that the membrane-proximal cytoplasmic domain of Sema4D contains a binding site for calmodulin within the polybasic region Arg762-Lys779. Coprecipitation studies show that Sema4D and calmodulin are associated in resting platelets, forming a complex that dissociates upon platelet activation by the agonists that trigger Sema4D cleavage. Inhibiting calmodulin with W7 or introducing a membrane-permeable peptide corresponding to the calmodulin-binding site is sufficient to trigger the dissociation of Sema4D from calmodulin and initiate cleavage. Conversely, deletion of the calmodulin-binding site causes constitutive shedding of Sema4D. These results show that (1) Sema4D is a calmodulin-binding protein with a site of interaction in its membrane-proximal cytoplasmic domain, (2) platelet agonists cause dissociation of the calmodulin-Sema4D complex, and (3) dissociation of the complex is sufficient to trigger ADAM17-dependent cleavage of Sema4D, releasing a bioactive fragment. (Blood. 2013;121(20):4221-4230) Introduction Sema4D (CD100), a class IV semaphorin family member, is a 150-kDa type I membrane glycoprotein. The mature protein is a disulfidelinked homodimer that includes an NH 2 -terminal (N-terminal) sema domain and a cytoplasmic domain containing sites for tyrosine and serine and/or threonine phosphorylation.1-5 Sema4D was first described on T cells where it supports B-cell differentiation by binding to the low-affinity receptor CD72. 3,[6][7][8] Subsequent studies have identified roles for Sema4D in axon guidance, 9-12 angiogenesis, [13][14][15][16][17] and tumor progression [18][19][20] and showed that some of these effects are mediated by the high-affinity receptor plexin-B1 20 and the related lower-affinity receptor plexin-B2. 21,22 In previously published studies, we have shown that Sema4D is expressed by platelets and that it participates in the hemostatic response to injury by reinforcing collagen-initiated platelet activation in a contact-dependent manner.23,24 Deletion of Sema4D protects mice against the development of atherosclerosis by attenuating platelet hyperactivity in the setting of hyperlipidemia 25 and reducing intimal neovascularization, 26 which suggests that platelet Sema4D has an impact on the vessel wall as well as on platelets. Our previous studies also showed that the extracellular domain of Sema4D is gradu...

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“…Several extrinsic cues have been found to influence the development of GABAergic interneurons, including neurotrophins, hepatocyte growth factor (HGF), semaphorins and neuregulin-1 (NRG-1) (Flames et al, 2004;Hirschberg et al, 2010;Marín et al, 2001;Polleux et al, 2002;Powell et al, 2001). Whereas semaphorins restrict the migration of MGE-derived interneurons, NRG-1 has been found to function as a cortex-derived chemoattractant by activation of the ErbB4 receptor in MGEderived neurons.…”

Section: Introductionmentioning

confidence: 99%

MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner

Perrinjaquet

Sjöstrand

Moliner

et al. 2011

Journal of Cell Science

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GDNF (glial cell line-derived neurotrophic factor) promotes the differentiation and migration of GABAergic neuronal precursors of the medial ganglionic eminence (MGE). These functions are dependent on the GPI-anchored receptor GFRα1, but independent of its two known transmembrane receptor partners RET and NCAM. Here we show that soluble GFRα1 is also able to promote differentiation and migration of GABAergic MGE neurons. These activities require endogenous production of GDNF. Although GDNF responsiveness is abolished in Gfra1−/− neurons, it can be restored upon addition of soluble GFRα1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons. The roles of two candidate transmembrane receptors previously implicated in GABAergic interneuron development - MET, a receptor for hepatocyte growth factor (HGF), and ErbB4, the neuregulin receptor – were examined. GDNF did not induce the activation of either receptor, nor did inhibition of MET or ErbB4 impair GDNF activity in GABAergic MGE neurons. Unexpectedly, however, inhibition of MET or HGF per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on MGE neurons. These effects were dependent on endogenous GDNF and GFRα1, suggesting that MET signaling negatively regulates GDNF activity in the MGE. In agreement with this, Met mutant MGE neurons showed enhanced responses to GDNF and inhibition of MET or HGF increased Gfra1 mRNA expression in MGE cells. In vivo, expression of MET and GFRα1 overlapped in the MGE, and a loss-of-function mutation in Met increased Gfra1 expression in this region. Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF–GFRα1 complex and uncover an unexpected interplay between GDNF–GFRα1 and HGF–MET signaling in the early diversification of cortical GABAergic interneuron subtypes.

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Gene Deletion Mutants Reveal a Role for Semaphorin Receptors of the Plexin-B Family in Mechanisms Underlying Corticogenesis

Cited by 42 publications

References 46 publications

Genetic dissection of plexin signaling in vivo

Genetic dissection of plexin signaling in vivo

Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets

MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner

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