Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion

Song, Lanying; Li, Yunhong; Wang, Kai; Wang, Yazhou; Molotkov, Andrei; Gao, Lifang; Zhao, Tianyu; Yamagami, Takashi; Wang, Yongping; Gan, Qini; Pleasure, David E; Zhou, Chengji J.

doi:10.1242/dev.037440

Cited by 142 publications

(194 citation statements)

References 54 publications

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“…Liu and Millar (2010) reported that the dynamic activation of the WNT/beta-catenin signaling pathway was correlated with the occurrence of a cleft lip and cleft palate. Song et al (2009) reported that cleft lip with cleft palate may be induced by genetic inactivation of Lrp6, a co-receptor of the WNT/beta-catenin signaling pathway. A previous case-control study associated mutations in AXIN2, a gene belonging to the WNT signaling pathway, with the occurrence of cleft lip/palate (Letra et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population

Yp¹,

Wt²,

Q³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Several WNT genes are involved in craniofacial embryogenesis, and therefore may play an important role in the etiology of NSCL/P. Two SNPs (rs3809857 and rs9890413) in the WNT3 gene were subjected to case-control and case-parent analysis by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 236 unrelated patients with NSCL/P, including 128 elementary families (185 mothers and 154 fathers), and 400 control individuals from northeast China. The rs3809857 SNP, under the assumption of a dominant model, was found to induce a 2-fold lower risk of NSCL/P OR GG vs GT + TT = 0.605, 95%CI = 0.436-0.839, P = 0.003). Moreover, the family-based association test revealed an under- 12647Variations in WNT3 are associated with orofacial clefts ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 12646-12653 (2015) transmission for the minor allele T. On the other hand, we observed a significant association in the case-control and case-parent analysis of the SNP rs9890413. In addition, the P values for the haplotype of rs3809857-rs9890413 were observed to be statistically significant (P = 0.004). In conclusion, our study confirmed the association between the WNT3 variant and NSCL/P in the population tested.

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Section: Discussionmentioning

confidence: 99%

Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population

Yp¹,

Wt²,

Q³

et al. 2015

Genet. Mol. Res.

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“…23 Pregnant dams were injected intraperitoneally with 200 mg/kg/day LiCl or the control NaCl solution on E8.5 to E11.5. The embryonic kidneys were dissected out at E12.5 for subsequent experiments.…”

Section: Maternal Administration Of Lithium Chloridementioning

confidence: 99%

“…Levels of mRNAs were normalized to glyceraldehyde-3-phosphate dehydrogenase (Gapdh) to allow comparisons among different experimental groups using the DCt method. 23 Chromatin Immunoprecipitation and Luciferase Reporter Assay…”

Section: Rna Isolation and Real-time Pcrmentioning

confidence: 99%

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LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Wang

Stokes

Duan

et al. 2016

Journal of the American Society of Nephrology

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Hypoplastic and/or cystic kidneys have been found in both LDL receptor-related protein 6 (Lrp6)-and b-catenin-mutant mouse embryos, and these proteins are key molecules for Wnt signaling. However, the underlying mechanisms of Lrp6/b-catenin signaling in renal development and cystic formation remain poorly understood. In this study, we found evidence that diminished cell proliferation and increased apoptosis occur before cystic dysplasia in the renal primordia of Lrp6-deficient mouse embryos. The expression of Ret protooncogene (Ret), a critical receptor for the growth factor glial cell line-derived neurotrophic factor (GDNF), which is required for early nephrogenesis, was dramatically diminished in the mutant renal primordia. The activities of other representative nephrogenic genes, including Lim1, Pax2, Pax8, GDNF, and Wnt11, were subsequently diminished in the mutant renal primordia. Molecular biology experiments demonstrated that Ret is a novel transcriptional target of Wnt/b-catenin signaling. Wnt agonist lithium promoted Ret expression in vitro and in vivo. Furthermore, Lrp6-knockdown or lithium treatment in vitro led to downregulation or upregulation, respectively, of the phosphorylated mitogen-activated protein kinases 1 and 3, which act downstream of GDNF/ Ret signaling. Mice with single and double mutations of Lrp6 and Ret were perinatal lethal and demonstrated gene dosage-dependent effects on the severity of renal hypoplasia during embryogenesis. Taken together, these results suggest that Lrp6-mediated Wnt/b-catenin signaling modulates or interacts with a signaling network consisting of Ret cascades and related nephrogenic factors for renal development, and the disruption of these genes or signaling activities may cause a spectrum of hypoplastic and cystic kidney disorders.

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“…In humans, mutations in VANGL1 have been associated with neural tube defects (Kibar et al, 2009;Kibar et al, 2007b). There is also an essential role for canonical Wnt signaling in the closure of the neural tube, palate, ventricular septum and ventral fissure of the eye, based on the phenotype of LDL-receptor related protein 6 (Lrp6) mutant mice (Pinson et al, 2000;Song et al, 2009;Song et al, 2010). It is not known whether this dependence on the canonical Wnt pathway principally reflects a requirement for rapid cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes

et al. 2010

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SUMMARYThe closure of an open anatomical structure by the directed growth and fusion of two tissue masses is a recurrent theme in mammalian embryology, and this process plays an integral role in the development of the palate, ventricular septum, neural tube, urethra, diaphragm and eye. In mice, targeted mutations of the genes encoding frizzled 1 (Fz1) and frizzled 2 (Fz2) show that these highly homologous integral membrane receptors play an essential and partially redundant role in closure of the palate and ventricular septum, and in the correct positioning of the cardiac outflow tract. When combined with a mutant allele of the planar cell polarity gene Vangl2 (Vangl2 Lp ), Fz1 and/or Fz2 mutations also cause defects in neural tube closure and misorientation of inner ear sensory hair cells. These observations indicate that frizzled signaling is involved in diverse tissue closure processes, defects in which account for some of the most common congenital anomalies in humans.KEY WORDS: Frizzled 1 (Fz1; Fzd1), Frizzled 2 (Fz2; Fzd2), Tissue closure, Mouse

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Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion

Cited by 142 publications

References 54 publications

Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population

Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes

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