Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

Wu, Haitao; Lu, Yanfeng; Shen, Chengyong; Patel, Neil; Gan, Lin; Xiong, Wen-Cheng; Mei, Lin

doi:10.1016/j.neuron.2012.04.033

Cited by 144 publications

(184 citation statements)

References 61 publications

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“…Deletion of MuSK CRD leads to severe alteration of both presynaptic and postsynaptic elements during early muscle prepatterning (E14) and NMJ differentiation (E18.5) mainly characterized by the following: (1) a drastic deficit in AChR clusters and (2) exuberant axonal growth bypassing AChR clusters. Moreover, MuSK CRD deletion is pathogenic in adult mice, inducing CMS-like symptoms, including kyphosis, NMJ dismantlement, muscle weakness, and fatigability as previously observed in other mice models of CMS (Gomez et al, 1997;Chevessier et al, 2008Chevessier et al, , 2012Bogdanik and Burgess, 2011;Webster et al, 2013). We also report that NMJ innervation defects in MuSK⌬CRD mice can be rescued in vivo by LiCl treatment.…”

Section: Discussionsupporting

confidence: 84%

“…8C). Because previous reports suggest that the Wnt canonical pathway is involved in neuromuscular synapse formation (Li et al, 2008;Liu et al, 2012;Wu et al, 2012a), we then reasoned that forced activation of the Wnt ␤-catenin signaling pathway during development could thwart impaired NMJ formation and compensate at least partially MuSK⌬CRD NMJ phenotype. To test this hypothesis, we set up a pharmacological approach using lithium chloride (LiCl), a wellknown reversible inhibitor of Gsk3 kinase and activator of Wnt/␤-catenin signaling (Klein and Melton, 1996;Stambolic et al, 1996;Wada, 2009).…”

Section: Lithium Chloride Rescues Nmj Phenotype Of Musk⌬crd Micementioning

confidence: 99%

“…The muscle-specific tyrosine kinase receptor MuSK and its coreceptor Lrp4 (low density lipoprotein receptor) constitute the central hub orchestrating all steps of NMJ formation and maintenance (Wu et al, 2010;. MuSK contains in its extracellular region a Frizzled-like domain (cysteine-rich domain [CRD]) mediating its interaction with several Wnts molecules, including Wnt4, Wnt11, and Wnt9a in vitro (Jing et al, 2009;.…”

Section: Introductionmentioning

confidence: 99%

“…MuSK contains in its extracellular region a Frizzled-like domain (cysteine-rich domain [CRD]) mediating its interaction with several Wnts molecules, including Wnt4, Wnt11, and Wnt9a in vitro (Jing et al, 2009;. Activation of the MuSK-Lrp4 complex regulates the prepatterning step, before muscle innervation, during which AChRs begin to aggregate in a broad central and prospective synaptic region of the muscle Yang et al, 2001;Arber et al, 2002;Weatherbee et al, 2006;Kim and Burden, 2008). Moreover, in vivo knockdown of Wnt4 and Wnt11 affects muscle prepatterning and axon guidance, indicating a role for Wnt signaling in this process (Jing et al, 2009;.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, in vivo knockdown of Wnt4 and Wnt11 affects muscle prepatterning and axon guidance, indicating a role for Wnt signaling in this process (Jing et al, 2009;. Upon innervation, the MuSK-Lrp4 complex is further stimulated by neural agrin, which induces multiple signaling pathways leading to clustering and remodeling of aneural AChR clusters (Kim et al, 2008;Wu et al, 2010). In addition to their role in prepatterning, Wnt proteins have been shown to regulate agrin-induced AChR clustering in vitro (Henriquez et al, 2008;.…”

Section: Introductionmentioning

confidence: 99%

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MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance

Messéant¹,

Dobbertin²,

Girard³

et al. 2015

J. Neurosci.

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The muscle-specific kinase MuSK is one of the key molecules orchestrating neuromuscular junction (NMJ) formation. MuSK interacts with the Wnt morphogens, through its Frizzled-like domain (cysteine-rich domain [CRD]). Dysfunction of MuSK CRD in patients hasbeen recently associated with the onset of myasthenia, common neuromuscular disorders mainly characterized by fatigable muscle weakness. However, the physiological role of Wnt-MuSK interaction in NMJ formation and function remains to be elucidated. Here, we demonstrate that the CRD deletion of MuSK in mice caused profound defects of both muscle prepatterning, the first step of NMJ formation, and synapse differentiation associated with a drastic deficit in AChR clusters and excessive growth of motor axons that bypass AChR clusters. Moreover, adult MuSK⌬CRD mice developed signs of congenital myasthenia, including severe NMJs dismantlement, muscle weakness, and fatigability. We also report, for the first time, the beneficial effects of lithium chloride, a reversible inhibitor of the glycogen synthase kinase-3, that rescued NMJ defects in MuSK⌬CRD mice and therefore constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt-MuSK signaling pathway deficiency. Together, our data reveal that MuSK CRD is critical for NMJ formation and plays an unsuspected role in NMJ maintenance in adulthood.

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Section: Discussionsupporting

confidence: 84%

Section: Lithium Chloride Rescues Nmj Phenotype Of Musk⌬crd Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance

Messéant¹,

Dobbertin²,

Girard³

et al. 2015

J. Neurosci.

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LRP 4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients

Tzartos

Zisimopoulou

Rentzos

et al. 2013

Ann Clin Transl Neurol

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ObjectiveAmyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG) are caused, respectively, by motor neuron degeneration and neuromuscular junction (NMJ) dysfunction. The membrane protein LRP4 is crucial in the development and function of motor neurons and NMJs and LRP4 autoantibodies have been recently detected in some MG patients. Because of the critical role in motor neuron function we searched for LRP4 antibodies in ALS patients.MethodsWe developed a cell-based assay and a radioimmunoassay and with these we studied the sera from 104 ALS patients.ResultsLRP4 autoantibodies were detected in sera from 24/104 (23.4%) ALS patients from Greece (12/51) and Italy (12/53), but only in 5/138 (3.6%) sera from patients with other neurological diseases and 0/40 sera from healthy controls. The presence of LRP4 autoantibodies in five of six tested patients was persistent for at least 10 months. Cerebrospinal fluid samples from six of seven tested LRP4 antibody-seropositive ALS patients were also positive. No autoantibodies to other MG autoantigens (AChR and MuSK) were detected in ALS patients. No differences in clinical pattern were seen between ALS patients with or without LRP4 antibodies.ConclusionsWe infer that LRP4 autoantibodies are involved in patients with neurological manifestations affecting LRP4-containing tissues and are found more frequently in ALS patients than MG patients. LRP4 antibodies may have a direct pathogenic activity in ALS by participating in the denervation process.

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Sclerostin Influences Exercise-Induced Adaptations in Body Composition and White Adipose Tissue Morphology in Male Mice

Kurgan

Stoikos

Baranowski

et al. 2020

Journal of Bone and Mineral Research

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Sclerostin is an inhibitor of the osteogenic Wnt/β‐catenin signaling pathway that also has an endocrine role in regulating adipocyte differentiation and metabolism. Additionally, subcutaneous white adipose tissue (scWAT) sclerostin content decreases following exercise training (EXT). Therefore, we hypothesized that EXT‐induced reductions in adipose tissue sclerostin may play a role in regulating adaptations in body composition and whole‐body metabolism. To test this hypothesis, 10‐week‐old male C57BL/6J mice were either sedentary (SED) or performing 1 hour of treadmill running at ~65% to 70% maximum oxygen consumption (VO2max) 5 day/week (EXT) for 4 weeks and had subcutaneous injections of either saline (C) or recombinant sclerostin (S) (0.1 mg/kg body mass) 5 day/week; thus, making four groups (SED‐C, EXT‐C, SED‐S, and EXT‐S; n = 12/group). No differences in body mass were observed between experimental groups, whereas food intake was higher in EXT (p = 0.03) and S (p = 0.08) groups. There was a higher resting energy expenditure in all groups compared to SED‐C. EXT‐C had increased lean mass and decreased fat mass percentage compared to SED‐C and SED‐S. No differences in body composition were observed in either the SED‐S or EXT‐S groups. Lower scWAT (inguinal), epididymal white adipose tissue (eWAT) (visceral epididymal) mass, and scWAT adipocyte cell size and increased percentage of multilocular cells in scWAT were observed in the EXT‐C group compared to SED‐C, whereas lower eWAT was only observed in the EXT‐S group. EXT mice had increased scWAT low‐density lipoprotein receptor‐related protein 4 (Lrp4) and mitochondrial content and sclerostin treatment only inhibited increased Lrp4 content with EXT. Together, these results provide evidence that reductions in resting sclerostin with exercise training may influence associated alterations in energy metabolism and body composition, particularly in scWAT. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

Cited by 144 publications

References 61 publications

MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance

MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance

LRP 4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients

Sclerostin Influences Exercise-Induced Adaptations in Body Composition and White Adipose Tissue Morphology in Male Mice

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