A synaptic nidogen: Developmental regulation and role of nidogen-2 at the neuromuscular junction

Fox, Michael A.; Ho, Mandy; Smyth, Neil; Sanes, Joshua R.

doi:10.1186/1749-8104-3-24

Cited by 48 publications

(43 citation statements)

References 81 publications

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“…6). Similar defects are also observed in mutants for laminin-α4, collagen IV (the α5 chain), collagen XIII and nidogen-2, suggesting that interactions between a range of basal lamina proteins and integrins may be important for synaptic maintenance (Fox et al, 2007(Fox et al, , 2008Latvanlehto et al, 2010;Samuel et al, 2012). Consistent with this finding is altered autophagy (Fig.…”

Section: Role Of Integrin-α3 In Nmj Maintenancesupporting

confidence: 77%

“…Using these mice, and also heterozygotes, which survive after birth, we demonstrate that integrin-α3 plays a role in the localisation of AZ components and synaptic vesicle release at the NMJ. In addition, the NMJs of heterozygous mice progressively accumulate morphological features that are found in aged (∼2 year old) wild-type (WT) animals, and in a number of mouse models with neurodegeneration or NMJ defects, suggesting a role in synaptic maintenance (Fox et al, 2007(Fox et al, , 2008Latvanlehto et al, 2010;Samuel et al, 2012). Surprisingly, we also observed instances of localised detachment of presynaptic terminals from the basal lamina, suggesting that integrin-α3 mediates anchorage of the pre-and postsynaptic elements at the NMJ.…”

Section: Introductionmentioning

confidence: 70%

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Multiple roles of integrin-α3 at the neuromuscular junction

Ross

Webster

Lechertier

et al. 2017

Journal of Cell Science

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The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-α3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-α3 also regulates integrity of the synapse -mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre-and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-α3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing.

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Section: Role Of Integrin-α3 In Nmj Maintenancesupporting

confidence: 77%

Section: Introductionmentioning

confidence: 70%

Multiple roles of integrin-α3 at the neuromuscular junction

Ross

Webster

Lechertier

et al. 2017

Journal of Cell Science

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“…Several transmembrane eLRRon proteins, including mammalian LRRTM1-3 and Drosophila capricious and tartan, promote synaptic junction formation or maintenance (Kurusu et al, 2008;ShinzaKameda et al, 2006;Shishido et al, 1998;Taniguchi et al, 2000). Although synaptic junctions can be influenced by the ECM (Ackley et al, 2003;Fox et al, 2008) C. elegans eLRRon proteins reveal a link between apical ECM organization and epithelial junction maintenance We showed here that the TM eLRRon proteins LET-4 and EGG-6 and their secreted paralog SYM-1 are required for both apical ECM organization and epithelial junction stability in the C. elegans epidermis and excretory duct and pore tubes. Potentially, these eLRRon proteins could play independent roles in both processes or could act in some common upstream process such as protein trafficking.…”

Section: Known Roles For Elrron Proteins In Matrix and Junction Organmentioning

confidence: 99%

Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity inC. elegans

et al. 2012

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SUMMARYEpithelial cells are linked by apicolateral junctions that are essential for tissue integrity. Epithelial cells also secrete a specialized apical extracellular matrix (ECM) that serves as a protective barrier. Some components of the apical ECM, such as mucins, can influence epithelial junction remodeling and disassembly during epithelial-to-mesenchymal transition (EMT). However, the molecular composition and biological roles of the apical ECM are not well understood. We identified a set of extracellular leucine-rich repeat only (eLRRon) proteins in C. elegans (LET-4 and EGG-6) that are expressed on the apical surfaces of epidermal cells and some tubular epithelia, including the excretory duct and pore. A previously characterized paralog, SYM-1, is also expressed in epidermal cells and secreted into the apical ECM. Related mammalian eLRRon proteins, such as decorin or LRRTM1-3, influence stromal ECM or synaptic junction organization, respectively. Mutants lacking one or more of the C. elegans epithelial eLRRon proteins show multiple defects in apical ECM organization, consistent with these proteins contributing to the embryonic sheath and cuticular ECM. Furthermore, epithelial junctions initially form in the correct locations, but then rupture at the time of cuticle secretion and remodeling of cell-matrix interactions. This work identifies epithelial eLRRon proteins as important components and organizers of the pre-cuticular and cuticular apical ECM, and adds to the small but growing body of evidence linking the apical ECM to epithelial junction stability. We propose that eLRRon-dependent apical ECM organization contributes to cell-cell adhesion and may modulate epithelial junction dynamics in both normal and disease situations.

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“…In contrast, relatively little is known about the molecular machinery that orchestrates postnatal postsynaptic maturation, perhaps in part because this process is likely to be more complicated than initial aggregation (Shi et al, 2012). Proteins that have been implicated include components of the extracellular matrix that runs through the synaptic cleft [laminins, collagens and nidogens (Fox et al, 2007;Fox et al, 2008;Latvanlehto et al, 2010;Nishimune et al, 2008;Shi et al, 2012)], the guanine exchange factor (GEF) ephexin-1 (Shi et al, 2010a;Shi et al, 2010b), and components of the dystrophin glycoprotein complex such as dystrobrevin (Grady et al, 2000;Grady et al, 2003). Interestingly, several of these proteins have also been implicated in plasticity of synapses the central nervous system (Fu et al, 2007;Michaluk et al, 2007;Shi et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%

Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle

Prószyński

Sanes²

2013

Journal of Cell Science

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SummaryNeuromuscular junctions (NMJs) in mammalian skeletal muscle undergo a postnatal topological transformation from a simple oval plaque to a complex branched structure. We previously showed that podosomes, actin-rich adhesive organelles, promote the remodeling process, and demonstrated a key role for one podosome component, LL5b. To further investigate molecular mechanisms of postsynaptic maturation, we purified LL5b-associated proteins from myotubes and showed that three regulators of the actin cytoskeleton -Amotl2, Asef2 and Flii -interact with LL5b. These and other LL5b-interacting proteins are associated with conventional podosomes in macrophages and podosome-like invadopodia in fibroblasts, strengthening the close relationship between synaptic and non-synaptic podosomes. We then focused on Amotl2, showing that it is associated with synaptic podosomes in cultured myotubes and with NMJs in vivo. Depletion of Amotl2 in myotubes leads to increased size of synaptic podosomes and corresponding alterations in postsynaptic topology. Depletion of Amotl2 from fibroblasts disrupts invadopodia in these cells. These results demonstrate a role for Amotl2 in synaptic maturation and support the involvement of podosomes in this process.

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A synaptic nidogen: Developmental regulation and role of nidogen-2 at the neuromuscular junction

Cited by 48 publications

References 81 publications

Multiple roles of integrin-α3 at the neuromuscular junction

Multiple roles of integrin-α3 at the neuromuscular junction

Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity inC. elegans

Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle

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