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  Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis

Kokubu, C., Heinzmann, U., Kokubu, T., Sakai, N., Kubota, T., Kawai, M., et al. (2004). Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development, 131, 5469-5480. doi:10.1242/dev.01405.

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Kokuba 2004_Development.pdf (Publisher version), 776KB
 
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https://dev.biologists.org/content/131/21/5469 (Publisher version)
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 Creators:
Kokubu, Chikara1, Author
Heinzmann, Ulrich1, Author
Kokubu, Tomoko1, Author
Sakai, Norio1, Author
Kubota, Takuo1, Author
Kawai, Masanobu1, Author
Wahl, Matthias B1, Author
Galceran, Juan1, Author
Grosschedl, Rudolf2, Author              
Ozono, Keiichi1, Author
Imai, Kenji1, Author
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1External Organizations, ou_persistent22              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              

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Free keywords: Lrp6, Wnt signaling, Somitogenesis, Osteoporosis, Mouse
 Abstract: Here, we present evidence that Lrp6, a coreceptor for Wnt ligands, is required for the normal formation of somites and bones. By positional cloning, we demonstrate that a novel spontaneous mutation ringelschwanz (rs) in the mouse is caused by a point mutation in Lrp6, leading to an amino acid substitution of tryptophan for the evolutionarily conserved residue arginine at codon 886 (R886W). We show that rs is a hypomorphic Lrp6 allele by a genetic complementation test with Lrp6-null mice, and that the mutated protein cannot efficiently transduce signals through the Wnt/β-catenin pathway. Homozygous rs mice, many of which are remarkably viable, exhibit a combination of multiple Wnt-deficient phenotypes, including dysmorphologies of the axial skeleton, digits and the neural tube. The establishment of the anteroposterior somite compartments, the epithelialization of nascent somites, and the formation of segment borders are disturbed in rs mutants, leading to a characteristic form of vertebral malformations, similar to dysmorphologies in individuals suffering from spondylocostal dysostosis. Marker expression study suggests that Lrp6 is required for the crosstalk between the Wnt and notch-delta signaling pathways during somitogenesis. Furthermore, the Lrp6 dysfunction in rs leads to delayed ossification at birth and to a low bone mass phenotype in adults. Together, we propose that Lrp6 is one of the key genetic components for the pathogenesis of vertebral segmentation defects and of osteoporosis in humans.

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Language(s): eng - English
 Dates: 2004-11
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1242/dev.01405
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Title: Development
  Other : Development
Source Genre: Journal
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Publ. Info: Cambridge, Cambridgeshire : Company of Biologists
Pages: - Volume / Issue: 131 Sequence Number: - Start / End Page: 5469 - 5480 Identifier: ISSN: 0950-1991
CoNE: https://pure.mpg.de/cone/journals/resource/954927546241