Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis.
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/beta-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.
Kokubu
Chikara
C
Institute of Developmental Genetics, GSF-National Research Center for Environment and Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
Heinzmann
Ulrich
U
Kokubu
Tomoko
T
Sakai
Norio
N
Kubota
Takuo
T
Kawai
Masanobu
M
Wahl
Matthias B
MB
Galceran
Juan
J
Grosschedl
Rudolf
R
Ozono
Keiichi
K
Imai
Kenji
K
D000375:Aging / Q000502:physiology; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning / Q000235:genetics; D016764:Cell Polarity; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005347:Fibroblasts; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008161:Lumbosacral Region / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009139:Musculoskeletal Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D019170:Somites / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin
D051792:Basic Helix-Loop-Helix Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C555475:LRP6 protein, human; C555476:Lrp6 protein, mouse; C093234:Tcf15 protein, mouse