APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

Choi, Hong Y.; Liu, Yun; Christian, Tennert; Sugiura, Yoshie; Karakatsani, Andromachi; Kröger, Stephan; Johnson, Eric B.; Hammer, Robert E.; Lin, Weichun; Herz, Joachim

doi:10.7554/elife.00220

Cited by 61 publications

(78 citation statements)

References 71 publications

(120 reference statements)

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“…One intriguing possibility is that APP controls lipoprotein metabolism via interactions with LRPs such as LDLRrelated protein 1 (LRP1) (Kounnas et al, 1995;Trommsdorff et al, 1998), LRP1B (Cam et al, 2004), Megalin (or LRP2) (Alvira-Botero et al, 2010), MEGF7 (or LRP4) (Choi et al, 2013), very low-density lipoprotein receptor (VLDLR) (Dumanis et al, 2012), Apoer2 (or LRP8) (Hoe et al, 2005), SorlA (or SORL1/ LR11) (Andersen et al, 2005), and LRAD3 (Ranganathan et al, 2011). Many of the LRPs are also g-secretase substrates (Haapasalo and Kovacs, 2011), and LRPs themselves could regulate APP trafficking and processing (Marzolo and Bu, 2009), indicating that APP might couple synaptic activity with lipid flux.…”

Section: Reviewmentioning

confidence: 99%

“…APP knockout mice also display decreased locomotor activity and forelimb strength, pointing to a possible role for APP at the NMJ (Zheng et al, 1995). The mechanism of APP function at the NMJ is not well understood, but could act at least in part through LDL receptor-related protein 4 (LRP4) (Choi et al, 2013). LRP4 is a receptor for agrin (a regulator of synaptogenesis), which is required for normal NMJ formation (Yumoto et al, 2012).…”

Section: Reviewmentioning

confidence: 99%

“…Interestingly, in this context, agrin fragment levels are regulated by g-secretase control of neurotrypsin expression (Almenar-Queralt et al, 2013). APP, agrin, and LRP4 interact and are capable of activating muscle-specific tyrosine kinase (MuSK) triggering acetylcholine receptor clustering and thereby shaping NMJ function, indicating that APP has an important role in the formation or maintenance of the NMJ (Choi et al, 2013).…”

Section: Reviewmentioning

confidence: 99%

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Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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Amyloid precursor protein (APP) is a key player in Alzheimer's disease (AD). The Aβ fragments of APP are the major constituent of AD-associated amyloid plaques, and mutations or duplications of the gene coding for APP can cause familial AD. Here we review the roles of APP in neuronal development, signaling, intracellular transport, and other aspects of neuronal homeostasis. We suggest that APP acts as a signaling nexus that transduces information about a range of extracellular conditions, including neuronal damage, to induction of intracellular signaling events. Subtle disruptions of APP signaling functions may be major contributors to AD-causing neuronal dysfunction.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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“…It has been shown that the ICD is dispensable for Lrp4 function in the neuromuscular junction as a receptor for agrin (Choi et al, 2013;Gomez and Burden, 2011). In this regard, it is unclear whether the tooth defects of Lrp4 ECD/ECD mice result from lack of anchorage to the cell membrane or from lack of ICD.…”

Section: Gain-and Loss-of-function In Vivo Studies Support Domainspecmentioning

confidence: 82%

Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

et al. 2017

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During development and homeostasis, precise control of Wnt/β-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/β-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/β-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/β-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.

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“…Many key components responsible for assembling the postsynaptic apparatus and its acetylcholine receptors (AChRs) have been already identified (Choi et al, 2013;Darabid et al, 2014;Hallock et al, 2010;Shi et al, 2012). Less is known about mechanisms that orchestrate postnatal remodeling of NMJs (Shi et al, 2012); however, the dystrophin-associated glycoprotein complex (DGC) has emerged as a key player.…”

Section: Introductionmentioning

confidence: 99%

α-Dystrobrevin-1 recruits Grb2 and α-catulin to organize neurotransmitter receptors at the neuromuscular junction

Gingras

Gawor

Bernadzki

et al. 2016

Journal of Cell Science

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Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development but undergo substantial remodeling postnatally. Several lines of evidence suggest that α-dystrobrevin, a component of the dystrophinassociated glycoprotein complex (DGC), is a crucial regulator of the remodeling process and that tyrosine phosphorylation of one isoform, α-dystrobrevin-1, is required for its function at synapses. We identified a functionally important phosphorylation site on α-dystrobrevin-1, generated phosphorylation-specific antibodies to it and used them to demonstrate dramatic increases in phosphorylation during the remodeling period, as well as in nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phosphorylation-dependent manner and others that bind to α-dystrobrevin-1 in a phosphorylation-independent manner. They include multiple members of the DGC, as well as α-catulin, liprin-α1, Usp9x, PI3K, Arhgef5 and Grb2. Finally, we show that two interactors, α-catulin ( phosphorylation independent) and Grb2 ( phosphorylation dependent) are localized to NMJs in vivo, and that they are required for proper organization of neurotransmitter receptors on myotubes.

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APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

Cited by 61 publications

References 71 publications

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

α-Dystrobrevin-1 recruits Grb2 and α-catulin to organize neurotransmitter receptors at the neuromuscular junction

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