Expression of mouse agrin in normal, denervated and dystrophic muscle

Eusebio, Alexander; Oliveri, Filippo; Barzaghi, Patrizia; Rüegg, Markus A.

doi:10.1016/s0960-8966(03)00036-1

Cited by 42 publications

(31 citation statements)

References 57 publications

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“…In vitro adhesion assays for MZ and FO B cells were performed as previously described (10) using the following substrates: purified laminin 511/521 (47) and recombinant agrin (43), as representatives of ECM molecules enriched in the marginal zone; fibronectin, which is present in the marginal zone and the RP; and VCAM-1 (ADP5; R&D Systems), which has previously been identified as an adhesive substrate for splenocytes (10). Recombinant laminin α5 fragments were used to define binding domains (domains IVa, G4-G5, V-VI) (23).…”

Section: Methodsmentioning

confidence: 99%

Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival

Song

Lokmic

Lämmermann

et al. 2013

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

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We describe a unique extracellular matrix (ECM) niche in the spleen, the marginal zone (MZ), characterized by the basement membrane glycoproteins, laminin α5 and agrin, that promotes formation of a specialized population of MZ B lymphocytes that respond rapidly to blood-borne antigens. Mice with reduced laminin α5 expression show reduced MZ B cells and increased numbers of newly formed (NF) transitional B cells that migrate from the bone marrow, without changes in other immune or stromal cell compartments. Transient integrin α6β1-mediated interaction of NF B cells with laminin α5 in the MZ supports the MZ B-cell population, their long-term survival, and antibody response. Data suggest that the unique 3D structure and biochemical composition of the ECM of lymphoid organs impacts on immune cell fate.B-cell development | immunology S econdary lymphoid organs are characterized by their unique patterns of immune cell compartmentalization, which is important for their function. Over recent years, the molecular basis for these distinct compartments within lymph nodes and the spleen has been intensely studied, revealing a complex interrelationship between cell-cell adhesion molecules, cytokines, and chemotactic factors. Most such adhesive and chemotactic factors are expressed by the stromal cells of the nonhematopoietic scaffold of secondary lymphoid organs, which constitute the reticular fiber network. However, little attention has been given to the acellular component of the reticular fiber network, and relatively little is known about the nature of this extracellular matrix (ECM) compartment and its function. In most tissues the ECM acts to separate cellular compartments and provides scaffolds for the adhesion and migration of cells, in the form of basement membranes or fibrillar interstitial matrices; it provides molecular cues that control differentiation and proliferation processes and determines cell survival vs. cell death (anoikis), either by direct interaction with cells or indirectly due to its large potential to bind and present cytokines and chemotactic factors (1). Whether similar functions exist in secondary lymphoid organs remains largely univestigated.The reticular fiber network consists of an inner core of fibrillar collagens, ensheathed by a basement membrane layer and microfibrillar proteins, and an outer layer of reticular fibroblasts (2-4). However, the molecular constituents of these layers vary in reticular fibers of different cellular compartments, and fundamental differences exist between the lymph node and spleen (4). Apart from acting as the structural backbone and potentially also a scaffold for immigrating cells (5), the reticular fiber network functions as a conduit for small-molecular-weight (<70 kDa) soluble factors (3, 6), which, in the lymph node, permit rapid delivery of antigens and/or chemokines (5) from the periphery to the surface of high endothelial venules for recruitment of T lymphocytes (2, 3). Whether other functions exist is not clear.Our work focuses on the ECM of the splee...

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Section: Methodsmentioning

confidence: 99%

Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival

Song

Lokmic

Lämmermann

et al. 2013

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

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“…6C). These polyclonal antibodies were generated against a 95 kDa C-terminal fragment of mouse agrin (Eusebio et al, 2003), which has been shown to be responsible for LRP4 binding and acetylcholine receptor aggregation at the NMJ. Neurons overexpressing LRP4 had reduced numbers of spines (Fig.…”

Section: Knockdown Of Lrp4 Reduces the Number Of Direct Presynaptic Pmentioning

confidence: 99%

“…The number of transfected cells was in the range of 2% and the efficiency was similar for each of the vectors used. One day after transfection, neurons were treated with 16 U chick agrin (C-terminal 125 kDa fragment isoform A4B8; Pevzner et al, 2012) or with 0.6 μl rabbit polyclonal anti-agrin antibody (serum 204; Eusebio et al, 2003) in 0.5 ml culture medium. We observed no effect of the antibodies on cell death and number of neurons and non-neuronal cells in the cultures.…”

Section: Neuronal Cultures Transfection Cell Treatments and Immunocmentioning

confidence: 99%

Neuronal LRP4 regulates synapse formation in the developing CNS

et al. 2017

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The low-density lipoprotein receptor-related protein 4 (LRP4) is essential in muscle fibers for the establishment of the neuromuscular junction. Here, we show that LRP4 is also expressed by embryonic cortical and hippocampal neurons, and that downregulation of LRP4 in these neurons causes a reduction in density of synapses and number of primary dendrites. Accordingly, overexpression of LRP4 in cultured neurons had the opposite effect inducing more but shorter primary dendrites with an increased number of spines. Transsynaptic tracing mediated by rabies virus revealed a reduced number of neurons presynaptic to the cortical neurons in which LRP4 was knocked down. Moreover, neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA in vivo also resulted in neurons with fewer primary dendrites and a lower density of spines in the developing cortex and hippocampus. Collectively, our results demonstrate an essential and novel role of neuronal LRP4 in dendritic development and synaptogenesis in the CNS.

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“…Anti-agrin antibodies included rabbit antisera raised against the C-terminal half of chick (Gesemann et al, 1995) or mouse (Eusebio et al, 2003) agrin and the mouse monoclonal antibody 5B1 (Reist et al, 1987). Antibodies to the ␣1 or the ␣2 subunits of GABA A receptors were raised in guinea pigs and were a kind gift from J.-M. Fritschy (University of Zurich, Zurich, Switzerland).…”

Section: Generation Of Tg/agrnmentioning

confidence: 99%

“…Moreover, neurons in the CNS have been shown to express mRNA encoding agrin isoforms that contain amino acid inserts at the B/z site (O'Connor et al, 1994;Stone and Nikolics, 1995). Because we focused in this work on the role of agrin at synapses, we first examined the distribution of agrin in different regions of the adult brain that are rich in synapses using antibodies raised against mouse agrin (Eusebio et al, 2003). We examined the neuropil of the CA3 region, the dentate gyrus, and the cortex, where we found agrin-like immunoreactivity associated in puncta (Fig.…”

Section: Agrin Localizes To Excitatory But Not Inhibitory Synapses Inmentioning

confidence: 99%

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

Ksiazek¹,

Burkhardt²,

Lin³

et al. 2007

J. Neurosci.

107

111

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Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5-to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.

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Expression of mouse agrin in normal, denervated and dystrophic muscle

Cited by 42 publications

References 57 publications

Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival

Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival

Neuronal LRP4 regulates synapse formation in the developing CNS

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

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