{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Low‐density lipoprotein receptor‐related protein 4 (LRP4) is a multifunctional, single‐pass transmembrane protein that plays critical roles in both neuromuscular synapse formation and embryonic development. In muscle, LRP4 serves as a coreceptor for neural agrin, and its extracellular domain binds agrin to promote the activation of the muscle‐specific receptor tyrosine kinase (MuSK). This activation cascade triggers the clustering of acetylcholine receptors and the differentiation of both pre‐ and postsynaptic compartments at the neuromuscular junction (NMJ)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": " Notably, studies have demonstrated that the intracellular region of LRP4 is dispensable for agrin-induced MuSK phosphorylation and NMJ formation, whereas proper glycosylation and cell-surface localization—mediated by chaperones such as Mesdc2—are essential for its function.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its central role at the NMJ, LRP4 modulates key developmental signaling pathways. It functions as an important integrator of signals by interacting with factors that regulate Wnt/β-catenin and bone morphogenetic protein (BMP) pathways. In dental, limb, and kidney tissues, LRP4 binds to secreted antagonists (for example, Wise) and other ligands to fine-tune morphogenesis, with its regulatory actions influencing digit formation, tooth development, and overall skeletal patterning."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, functional studies in zebrafish and cellular models have revealed that LRP4 also acts to suppress aberrant Notch signaling and can modulate Wnt activity—findings that help explain why mutations in distinct domains of LRP4 give rise to a spectrum of disorders. For example, mutations affecting the beta-propeller domains can selectively impair agrin/MuSK signaling in the NMJ and contribute to congenital myasthenic syndromes, while other mutations compromise its ability to regulate Wnt signaling and are associated with limb malformations such as Cenani–Lenz syndactyly."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}, {"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, LRP4 functions as a pivotal signaling nexus that not only mediates essential agrin-induced MuSK activation to orchestrate NMJ formation but also modulates multiple developmental pathways—including Wnt, BMP, and Notch signaling—to ensure proper limb, tooth, and kidney morphogenesis. Disruption of these finely tuned processes through mutations in LRP4 underlies a range of neuromuscular and skeletal developmental disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bin Zhang, Shiwen Luo, Qiang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRP4 serves as a coreceptor of agrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2008.10.006"}], "href": "https://doi.org/10.1016/j.neuron.2008.10.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18957220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18957220"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Scott D Weatherbee, Kathryn V Anderson, Lee A Niswander "}, {"type": "b", "children": [{"type": "t", "text": "LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.02696"}], "href": "https://doi.org/10.1242/dev.02696"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17119023"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17119023"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Inga Koneczny, Judith Cossins, Patrick Waters, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0080695"}], "href": "https://doi.org/10.1371/journal.pone.0080695"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24244707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24244707"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bisei Ohkawara, Macarena Cabrera-Serrano, Tomohiko Nakata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt578"}], "href": "https://doi.org/10.1093/hmg/ddt578"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24234652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24234652"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Andrea M Gomez, Steven J Burden "}, {"type": "b", "children": [{"type": "t", "text": "The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.22772"}], "href": "https://doi.org/10.1002/dvdy.22772"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22038977"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22038977"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Taisuke Hoshi, Tohru Tezuka, Kazumasa Yokoyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesdc2 plays a key role in cell-surface expression of Lrp4 and postsynaptic specialization in myotubes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2013.10.001"}], "href": "https://doi.org/10.1016/j.febslet.2013.10.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24140340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24140340"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Atsushi Ohazama, Eric B Johnson, Masato S Ota, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lrp4 modulates extracellular integration of cell signaling pathways in development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0004092"}], "href": "https://doi.org/10.1371/journal.pone.0004092"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19116665"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19116665"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Eric B Johnson, Robert E Hammer, Joachim Herz "}, {"type": "b", "children": [{"type": "t", "text": "Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddi381"}], "href": "https://doi.org/10.1093/hmg/ddi381"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16207730"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16207730"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Dominique Simon-Chazottes, Sylvie Tutois, Michael Kuehn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2006.01.007"}], "href": "https://doi.org/10.1016/j.ygeno.2006.01.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16517118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16517118"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Tahir Naeem Khan, J Klar, Zafar Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2013.04.007"}], "href": "https://doi.org/10.1016/j.ejmg.2013.04.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23664847"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23664847"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jing Tian, Jinhui Shao, Cong Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-018-2928-3"}], "href": "https://doi.org/10.1007/s00018-018-2928-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30327840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30327840"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Rivka Sukenik Halevy, Huan-Chieh Chien, Bo Heinz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the fourth β-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.23417"}], "href": "https://doi.org/10.1002/humu.23417"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29524275"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29524275"}]}]}]}