The Amyotrophic Lateral Sclerosis 8 Protein VAPB Is Cleaved, Secreted, and Acts as a Ligand for Eph Receptors

Tsuda, Hiroshi; Han, Sung Min; Yang, Youfeng; Tong, Chao; Lin, Yong; Mohan, Kriti; Haueter, Claire; Zoghbi, Anthony W.; Harati, Yadollah; Kwan, Justin; Miller, Michael A.; Bellen, Hugo J.

doi:10.1016/j.cell.2008.04.039

Cited by 211 publications

(415 citation statements)

References 68 publications

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“…However, dysfunction of glial glutamate transporters has been implicated in epilepsy and ALS (4,6,28). Increased EphA4-ephrin interaction may therefore underlie some forms of ALS and the posttranscriptional down-regulation of GLT-1 observed in epileptic foci of the human brain (29)(30)(31). Our observations suggest that treatments to inhibit ephrin-A3 reverse signaling may increase glutamate transporter expression and have protective effects against epileptic seizures and glutamate excitotoxicity.…”

Section: Discussionmentioning

confidence: 77%

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Carmona

Murai

Wang

et al. 2009

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

184

173

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Increasing evidence indicates the importance of neuron-glia communication for synaptic function, but the mechanisms involved are not fully understood. We reported that the EphA4 receptor tyrosine kinase is in dendritic spines of pyramidal neurons of the adult hippocampus and regulates spine morphology. We now show that the ephrin-A3 ligand, which is located in the perisynaptic processes of astrocytes, is essential for maintaining EphA4 activation and normal spine morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.glial glutamate transporters ͉ hippocampus-dependent learning ͉ neuron-glia communication ͉ perisynaptic glial processes C ommunication between neurons and astrocytes plays an important role in synapse development and physiology. During development, astrocytes promote synapse formation and maturation (1, 2). Later on, astrocytes are actively involved in synaptic transmission by responding to synaptic activation and releasing gliotransmitters, which in turn modulate neuronal excitability and neurotransmission (1, 3). At excitatory synapses, astrocytes clear the majority of glutamate released into the synaptic cleft through their high-affinity transporters, GLAST and GLT-1 (4). This function is crucial for fine-tuning glutamatergic transmission and prevents accumulation of toxic levels of extracellular glutamate (5-7). Despite their importance in glutamate homeostasis, very little is known about the molecular mechanisms that regulate the expression and cell surface localization of glial glutamate transporters.Several members of the Eph family of receptor tyrosine kinases (comprising EphA and EphB receptors) and their cell surface-associated ephrin ligands are expressed in neurons of the hippocampus and cerebral cortex, where they have been implicated in synapse formation and the regulation of synaptic function and plasticity (8, 9). Signaling by Eph receptors is also involved in the development of dendritic spines, the specialized protrusions on dendrites that receive excitatory innervation. Typical spines have an enlarged head connected to the dendritic shaft by a constricted neck. Activation of dendritic EphB receptors by ephrin-B ligands has been shown to induce spine morphogenesis and maturation (8, 9). EphA receptors are important regulators of spine morphology in the adult. We have reported that EphA4 is localized on dendritic spines of pyramidal neurons in the m...

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Section: Discussionmentioning

confidence: 77%

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Carmona

Murai

Wang

et al. 2009

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

184

173

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“…From the screen, two Drosophila VAP genes, dvap33a (Vap-33-1 -FlyBase) and fan, were identified as genetic interactors of Osbp. VAP33A has been shown to be involved in synaptic bouton formation at neuromuscular junctions and acts as a ligand for the Eph receptor (Pennetta et al, 2002;Tsuda et al, 2008). Post-eclosion behaviour defects resulting from Osbp overexpression were almost totally suppressed by co-expression of dvap33a (Fig.…”

Section: Research Articlementioning

confidence: 85%

OSBP- and FAN-mediated sterol requirement for spermatogenesis inDrosophila

Huang

2010

Development

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SUMMARYMembers of the oxysterol binding protein (OSBP) family are involved in diverse biological processes, including non-vesicular sterol transport and vesicle trafficking. The mechanisms by which OSBPs integrate functionally with developmental and physiological processes remain elusive. Here, we report the in vivo analysis of OSBP function in the model organism Drosophila. Osbp mutants are male-sterile and exhibit defects in individualization, the process by which each spermatid is packaged into its own membrane. Overexpression of OSBP leads to post-eclosion behaviour defects that can be suppressed by co-expression of endoplasmic reticulum-specific VAP family proteins. Most notably, FAN, a testis-specific VAP protein, acts together with OSBP genetically and physically to regulate the individualization process. OSBP-positive and sterol-enriched speckles are found at the leading edge of the individualization complex in wild type but not in Osbp or fan mutants, suggesting that sterol trafficking might play key roles during the membrane-remodelling phase of individualization. In addition, Osbp mutants that are fed additional sterols partially recover fertility, implying that male sterility is attributable to sterol shortage. Thus, we have identified an OSBP-and FANmediated sterol requirement in Drosophila spermatogenesis.

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“…By regulating intracellular transport, Notch signaling might operate over short distances to establish polarity within a cell. Likewise, Notch signaling might modulate responses to MSP-related ligands (Tsuda et al, 2008) in mammals. Thus, the findings reported here might have wider implications for the regulation of intercellular signaling, beyond the scope of the C. elegans germline.…”

Section: A Model For the Coordinate Control Of Oogenesis By Msp And Gmentioning

confidence: 99%

MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth inC. elegans

et al. 2009

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Fertility depends on germline stem cell proliferation, meiosis and gametogenesis, yet how these key transitions are coordinated is unclear. In C. elegans, we show that GLP-1/Notch signaling functions in the germline to modulate oocyte growth when sperm are available for fertilization and the major sperm protein (MSP) hormone is present. Reduction-of-function mutations in glp-1 cause oocytes to grow abnormally large when MSP is present and Gα s -adenylate cyclase signaling in the gonadal sheath cells is active. By contrast, gain-of-function glp-1 mutations lead to the production of small oocytes. Surprisingly, proper oocyte growth depends on distal tip cell signaling involving the redundant function of GLP-1 ligands LAG-2 and APX-1. GLP-1 signaling also affects two cellular oocyte growth processes, actomyosin-dependent cytoplasmic streaming and oocyte cellularization. glp-1 reduction-of-function mutants exhibit elevated rates of cytoplasmic streaming and delayed cellularization. GLP-1 signaling in oocyte growth depends in part on the downstream function of the FBF-1/2 PUF RNA-binding proteins. Furthermore, abnormal oocyte growth in glp-1 mutants, but not the inappropriate differentiation of germline stem cells, requires the function of the cell death pathway. The data support a model in which GLP-1 function in MSP-dependent oocyte growth is separable from its role in the proliferation versus meiotic entry decision. Thus, two major germline signaling centers, distal GLP-1 activation and proximal MSP signaling, coordinate several spatially and temporally distinct processes by which germline stem cells differentiate into functional oocytes.

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The Amyotrophic Lateral Sclerosis 8 Protein VAPB Is Cleaved, Secreted, and Acts as a Ligand for Eph Receptors

Cited by 211 publications

References 68 publications

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

OSBP- and FAN-mediated sterol requirement for spermatogenesis inDrosophila

MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth inC. elegans

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