Agrin in the Developing CNS: New Roles for a Synapse Organizer

Kröger, Stephan; Schröder, Jörn E.

doi:10.1152/nips.01390.2002

Cited by 31 publications

(35 citation statements)

References 22 publications

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“…Since similar processes can also be induced in nonneuronal cells from several species (22), 5 the intracellular signaling mechanism appears not to be restricted to neurons. Lipid rafts are glycosphingolipid-and cholesterol-enriched microdomains within cell membranes that serve as signaling platforms in many different cell types of many different species (30).…”

Section: Tm-agrin and Cholesterol-rich Lipid Rafts Colocalize Onmentioning

confidence: 99%

Transmembrane Form Agrin-induced Process Formation Requires Lipid Rafts and the Activation of Fyn and MAPK

Ramseger

White

Kröger

2009

Journal of Biological Chemistry

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Overexpression or clustering of the transmembrane form of the extracellular matrix heparan sulfate proteoglycan agrin (TM-agrin) induces the formation of highly dynamic filopodialike processes on axons and dendrites from central and peripheral nervous system-derived neurons. Here we show that the formation of these processes is paralleled by a partitioning of TM-agrin into lipid rafts, that lipid rafts and transmembraneagrin colocalize on the processes, that extraction of lipid rafts with methyl-␤-cyclodextrin leads to a dose-dependent reduction of process formation, that inhibition of lipid raft synthesis prevents process formation, and that the continuous presence of lipid rafts is required for the maintenance of the processes. Association of TM-agrin with lipid rafts results in the phosphorylation and activation of the Src family kinase Fyn and subsequently in the phosphorylation and activation of MAPK. Inhibition of Fyn or MAPK activation inhibits process formation. These results demonstrate that the formation of filopodia-like processes by TM-agrin is the result of the activation of a complex intracellular signaling cascade, supporting the hypothesis that TM-agrin is a receptor or coreceptor on neurons.Agrin is a proteoglycan with a molecular mass of more than 500 kDa that is expressed in many tissues (for a review, see Ref. 1). Despite its widespread expression, the function of agrin is best characterized in skeletal muscle, where it is a key organizer during formation, maintenance, and regeneration of the neuromuscular junction (2, 3). Accordingly, mice with an inactivation of the agrn gene die at birth due to nonfunctional neuromuscular junctions and subsequent respiratory failure (4).Little is known about the role of agrin in other tissues, in particular in the central nervous system (for a review, see Ref. 5). Although neurons from mice with a targeted deletion of the agrn gene form synaptic specializations in vitro and in vivo (6, 7), the acute suppression of agrin expression or function by antisense probes or antibodies influences the formation and function of interneuronal synapses (8, 9). Likewise, brains of agrin-deficient mice, whose perinatal death was prevented by the reexpression of agrin specifically in motor neurons, have a severely reduced number of pre-and postsynaptic specializations at excitatory synapses (10). In addition, agrin isoforms are highly expressed by central nervous system neurons before synapse formation, suggesting additional functions for agrin during axonal and dendritic elongation (11-16). Although these data are consistent with a role of agrin during CNS 4 synaptogenesis, the precise role of agrin during CNS development remains to be clarified.Alternative first exon usage generates either a secreted soluble agrin molecule (NtA-agrin) or a transmembrane form of agrin (TM-agrin) (17, 18). The secreted form of agrin specifically interacts with the laminin ␥1-chain via its NtA-domain, resulting in a stable association with basal laminae (19,20). In contrast, in TM-agrin, t...

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Section: Tm-agrin and Cholesterol-rich Lipid Rafts Colocalize Onmentioning

confidence: 99%

Transmembrane Form Agrin-induced Process Formation Requires Lipid Rafts and the Activation of Fyn and MAPK

Ramseger

White

Kröger

2009

Journal of Biological Chemistry

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“…In addition to motoneurons, agrin is expressed by all neuronal populations in the central nervous system (CNS), and is implicated to have potential functions in the formation and maturation of central synapses (Cohen et al, 1997;Kroger and Schroder, 2002;O'Connor et al, 1994;Rupp et al, 1991). In addition, the prominent expression of agrin in neurons during axonal growth prior to synapse formation suggests that it may have a presynaptic function, e.g.…”

Section: Introductionmentioning

confidence: 99%

Agrin regulates growth cone turning ofXenopusspinal motoneurons

et al. 2005

Development

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The pivotal role of agrin in inducing postsynaptic specializations at neuromuscular junctions has been well characterized. Increasing evidence suggests that agrin is also involved in neuronal development. In this study,we found that agrin inhibited neurite extension and, more importantly, a gradient of agrin induced repulsive growth-cone turning in cultured Xenopus spinal neurons. Incubation with a neutralizing antibody to agrin or expression of the extracellular domain of muscle-specific kinase, a component of the agrin receptor complex, abolished these effects of agrin. Agrin-induced repulsive growth-cone turning requires the activity of PI3-kinase and Ca2+ signaling. In addition, the expression of dominant-negative Rac1 inhibited neurite extension and blocked agrin-mediated growth-cone turning. Taken together, our findings suggest that agrin regulates neurite extension and provide evidence for an unanticipated role of agrin in growth-cone steering in developing neurons.

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“…Also, chromosomal aberrations involving this gene are associated with primary head and neck squamous cell tumors [28]. Agrn NM_021604 Agrn (M. musculus agrin): agrin is a neuronal aggregating factor that induces the aggregation of acetylcholine receptors and other postsynaptic proteins on muscle fibers and is crucial for the formation of the neuromuscular junction [29]. M. musculus splicing factor, arginine/serine-rich 6.…”

Section: Genetic Analysis Of Positive Clonesmentioning

confidence: 99%

Discovery of YB-1 as a new immunological target in neuroblastoma by vaccination in the context of regulatory T cell blockade

Zheng¹,

Jing²,

Orentas³

2009

ABBS

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Neuroblastoma is one of the most common solid tumors in infancy and early childhood. Using the A/J mouse and a syngeneic neuroblastoma cell line AGN2a, we induced a strong anti-neuroblastoma cellular immune response when AGN2a transfected to express costimulatory molecules (CD80/CD86/CD54/CD137L) was used as a vaccine in the context of regulatory T cell blockade. Strong humoral immunity was induced by AGN2a-4p immunization in the context with regulatory T cell blockade. Serum from treated mice was used to screen an AGN2a cDNA expression library that was constructed with l ZAP express vector in order to identify tumor-associated antigens by SEREX. Twentyone clones were identified by sequencing and comparative analysis of gene pools. Most transcripts play some roles in the neuronal differentiation, cell metabolism, or have previously been identified as transcripts that are over-expressed in other malignancies. The most commonly identified tumor-associated antigen, using serum from AGN2a-4p immunization with Treg blockade mice, was YB-1 protein that also induced a T cell response. These results indicated that potential neuroblastoma-associated antigens were found by the sera from mice immunized with tumor cells expressing costimulatory molecules with regulatory T cell function blockade. The identification of YB-1 as tumor-associated antigens capable of eliciting a T cell response validates our experimental approach and argues for the antigens we have identified here to be evaluated as targets of effector immunity and as vaccine candidates.

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Agrin in the Developing CNS: New Roles for a Synapse Organizer

Cited by 31 publications

References 22 publications

Transmembrane Form Agrin-induced Process Formation Requires Lipid Rafts and the Activation of Fyn and MAPK

Transmembrane Form Agrin-induced Process Formation Requires Lipid Rafts and the Activation of Fyn and MAPK

Agrin regulates growth cone turning ofXenopusspinal motoneurons

Discovery of YB-1 as a new immunological target in neuroblastoma by vaccination in the context of regulatory T cell blockade

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