Abstract
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 beta-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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Embryo, Mammalian / embryology
-
Embryo, Mammalian / metabolism
-
Folic Acid / pharmacology*
-
Gene Expression Regulation, Developmental
-
Humans
-
Intercellular Signaling Peptides and Proteins / metabolism*
-
Low Density Lipoprotein Receptor-Related Protein-6
-
Mice
-
Mice, Inbred DBA
-
Models, Animal
-
Models, Molecular
-
Molecular Sequence Data
-
Mutation / genetics
-
Neural Tube Defects / metabolism*
-
Protein Structure, Tertiary
-
Proteins / genetics
-
Proteins / metabolism
-
Receptors, LDL / chemistry
-
Receptors, LDL / genetics*
-
Receptors, LDL / metabolism*
-
Sequence Alignment
-
Tail / embryology*
-
Tail / growth & development
-
Tail / metabolism*
-
Wnt Proteins
Substances
-
DKK1 protein, human
-
Dkk1 protein, mouse
-
Intercellular Signaling Peptides and Proteins
-
LRP6 protein, human
-
Low Density Lipoprotein Receptor-Related Protein-6
-
Lrp6 protein, mouse
-
Proteins
-
Receptors, LDL
-
Wnt Proteins
-
Folic Acid