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Crooked tail ( Cd ) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6

2005; National Academy of Sciences; Volume: 102; Issue: 36 Linguagem: Inglês

10.1073/pnas.0501963102

1091-6490

Michelle Carter, Xu Chen, Bozena Slowinska, Sharon Minnerath, Sara B. Glickstein, Lei Shi, Fabien Campagne, Harel Weinstein, M. Elizabeth Ross,

Cancer-related gene regulation

A cranial neural tube defect in Crooked tail ( Cd ) mice is prevented with prenatal dietary folic acid Cd positional cloning reveals a missense mutation of a highly conserved amino acid in the low density lipoprotein receptor-related protein 6 ( Lrp6 ), a coreceptor required for Wnt canonical signaling. Molecular modeling predicts that Lrp6 Cd alters a hinge region of the second YWTD β-propeller domain. Mutant LRP6 binds to Wnt and Dickkopf1 (Dkk1) but not Mesd1, and Dkk1 cannot antagonize Wnt in Cd / Cd cells, resulting in hyperactivity. NIH 3T3 cells transfected with a mutant Lrp6 plasmid resist Dkk1 antagonism much like Cd /+ cells, confirming the significance of the mutation. The Lrp6 mutation in Cd mice provides evidence for a functional connection between Wnt signaling and folate rescue of neural tube defects.