The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice.
Recent work has identified LDL receptor-related family members, Lrp5 and Lrp6, as co-receptors for the transduction of Wnt signals. Our analysis of mice carrying mutations in both Lrp5 and Lrp6 demonstrates that the functions of these genes are redundant and are essential for gastrulation. Lrp5;Lrp6 double homozygous mutants fail to establish a primitive streak, although the anterior visceral endoderm and anterior epiblast fates are specified. Thus, Lrp5 and Lrp6 are required for posterior patterning of the epiblast, consistent with a role in transducing Wnt signals in the early embryo. Interestingly, Lrp5(+/-);Lrp6(-/-) embryos die shortly after gastrulation and exhibit an accumulation of cells at the primitive streak and a selective loss of paraxial mesoderm. A similar phenotype is observed in Fgf8 and Fgfr1 mutant embryos and provides genetic evidence in support of a molecular link between the Fgf and Wnt signaling pathways in patterning nascent mesoderm. Lrp5(+/-);Lrp6(-/-) embryos also display an expansion of anterior primitive streak derivatives and anterior neurectoderm that correlates with increased Nodal expression in these embryos. The effect of reducing, but not eliminating, Wnt signaling in Lrp5(+/-);Lrp6(-/-) mutant embryos provides important insight into the interplay between Wnt, Fgf and Nodal signals in patterning the early mouse embryo.
Kelly
Olivia G
OG
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3200, USA.
Pinson
Kathy I
KI
Skarnes
William C
WC
D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation; D017931:DNA Primers; D004707:Endoderm / Q000166:cytology / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000502:physiology; D005775:Gastrula / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins
D017931:DNA Primers; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors