ArticleHuman molecular genetics2014
Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2019Pooled it
- Exploring Ciliary Mechanisms in the Causation of Hydrocephalus in Humans-Similarities and Differences from Animal Models.Journal of molecular neuroscience : MN · 2025Review
- Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir.Frontiers in cell and developmental biology · 2023Article
- A quest for genetic causes underlying signaling pathways associated with neural tube defects.Frontiers in pediatrics · 2023Review
- Balancing WNT signalling in early forebrain development: The role of LRP4 as a modulator of LRP6 function.Frontiers in cell and developmental biology · 2023Article
- Wnt/planar cell polarity signaling controls morphogenetic movements of gastrulation and neural tube closure.Cellular and molecular life sciences : CMLS · 2022Review
- The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice.Disease models & mechanisms · 2022Article
- Review
- Loss of Zic3 impairs planar cell polarity leading to abnormal left-right signaling, heart defects and neural tube defects.Human molecular genetics · 2021Article
- MiR-21 Is Required for the Epithelial-Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells.International journal of molecular sciences · 2021Article
- Identification of Novel Variants in Cleft Palate-Associated Genes in Brazilian Patients With Non-syndromic Cleft Palate Only.Frontiers in cell and developmental biology · 2021Article
- Upregulated Wnt-11 and miR-21 Expression Trigger Epithelial Mesenchymal Transition in Aggressive Prostate Cancer Cells.Biology · 2020Article
- FZD10 regulates cell proliferation and mediates Wnt1 induced neurogenesis in the developing spinal cord.PloS one · 2020Article
- Comprehensive clinical and molecular studies in split-hand/foot malformation: identification of two plausible candidate genes (LRP6 and UBA2).European journal of human genetics : EJHG · 2019Article
- Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects.Cells · 2019Review
- Variants identified in PTK7 associated with neural tube defects.Molecular genetics & genomic medicine · 2019Article
- De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.Neuron · 2018Article
- Genetic analysis of Wnt/PCP genes in neural tube defects.BMC medical genomics · 2018Article
- ZIC3 in Heterotaxy.Advances in experimental medicine and biology · 2018Review
- Molecular genetics and targeted therapy of WNT-related human diseases (Review).International journal of molecular medicine · 2017Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Wnt signaling has been classified as canonical Wnt/β-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor-related protein Lrp6 is crucial for the activation of the Wnt/β-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26(m1Jus)) and in human NTDs. We demonstrate that Skax26(m1Jus) represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6(Skax26-Jus) genetically interacts with a PCP mutant (Vangl2(Lp)) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.