Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.
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.
Carter
Michelle
M
Department of Neurology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Chen
Xu
X
Slowinska
Bozena
B
Minnerath
Sharon
S
Glickstein
Sara
S
Shi
Lei
L
Campagne
Fabien
F
Weinstein
Harel
H
Ross
M Elizabeth
ME
D000595:Amino Acid Sequence; D000818:Animals; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D005492:Folic Acid / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008811:Mice, Inbred DBA; D023421:Models, Animal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009436:Neural Tube Defects / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D013623:Tail / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D051153:Wnt Proteins
C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011506:Proteins; D011973:Receptors, LDL; D051153:Wnt Proteins; D005492:Folic Acid