Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse

Simon-Chazottes, Dominique; Tutois, Sylvie; Kuehn, Michael R.; Evans, Martin; Bourgade, Franck; Cook, Susan A.; Davisson, Muriel T.; Guénet, Jean-Louis

doi:10.1016/j.ygeno.2006.01.007

Cited by 79 publications

(74 citation statements)

References 16 publications

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“…Lrp4 null mutations in mice result in limb development defects and in perinatal death due to a lack of neuromuscular junction formation (50). Animals with partial loss-of-function mutations (hypomorphic) are viable and present with different degrees of polysyndactyly (41,49). A recent study identified a role of Lrp4 in bone metabolism based on a mouse model harboring a stop , resulting in a R1170W substitution.…”

Section: Discussionmentioning

confidence: 99%

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

Leupin

Piters

Halleux

et al. 2011

Journal of Biological Chemistry

271

245

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Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. Although it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the underlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/␤-catenin signaling. We found the extracellular ␤-propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone.

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Section: Discussionmentioning

confidence: 99%

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

Leupin

Piters

Halleux

et al. 2011

Journal of Biological Chemistry

271

245

View full text Add to dashboard Cite

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“…Severe syndactyly and/or oligodactyly are common to all known Lrp4 mutant models and are attributed to disruption in AER patterning (Li et al, 2010;Pohlkamp et al, 2015;Simon-Chazottes et al, 2006;Weatherbee et al, 2006). Similarly, Lrp4 ΔICD/ΔICD mice display severe defects in distal limbs (Fig.…”

Section: Lrp4mentioning

confidence: 96%

“…TopGal, Lrp4 mitt , Lrp4 mte , Lrp4 mdig , Lrp4 ECD , Wise-null, Lrp5-null, Lrp6-null, K14-tTA and tetO-Wise mice were described previously (Ahn et al, 2013;DasGupta and Fuchs, 1999;Johnson et al, 2005;Kato et al, 2002;Pinson et al, 2000;Simon-Chazottes et al, 2006;Weatherbee et al, 2006) (Table S1). All experiments involving mice were performed under approved protocols issued to R.K. as the principal investigator by the Institutional Animal Care and Use Committee of the Stowers Institute for Medical Research (Protocol ID: 2016-0164).…”

Section: Mouse Strainsmentioning

confidence: 99%

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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“…Because Dkk1 is a negative regulator of WNT signaling that has a very dynamic domain of expression including the AER, the double ridge phenotype has been associated with enhanced canonical WNT signaling. In this regard, reduced or complete loss of Lrp4 (Johnson et al, 2005;Simon-Chazottes et al, 2006;Weatherbee et al, 2006), which also results in excessive canonical WNT signaling (Johnson et al, 2005;Weatherbee et al, 2006), produces phenotypes that are very similar to Dkk1 mutants. Furthermore, the Dkk1 phenotype was corrected by reduced expression of Lrp6 receptor (MacDonald et al, 2004).…”

Section: Altered Aer Morphologiesmentioning

confidence: 99%

The Apical Ectodermal Ridge: morphological aspects and signaling pathways

Fernandez-Teran¹,

Ros²

2008

Int. J. Dev. Biol.

125

133

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The Apical Ectodermal Ridge (AER) is one of the main signaling centers during limb development. It controls outgrowth and patterning in the proximo-distal axis. In the last few years a considerable amount of new data regarding the cellular and molecular mechanisms underlying AER function and structure has been obtained. In this review, we describe and discuss current knowledge of the regulatory networks which control the induction, maturation and regression of the AER, as well as the link between dorso-ventral patterning and the formation and position of the AER. Our aim is to integrate both recent and old knowledge to produce a wider picture of the AER which enhances our understanding of this relevant structure.

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Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse

Cited by 79 publications

References 16 publications

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

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

The Apical Ectodermal Ridge: morphological aspects and signaling pathways

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