Functional interactions between the LRP6 WNT co-receptor and folate supplementation

Area of Science:

• Developmental biology
• Genetics
• Biochemistry

Background:

• Crooked tail (Cd) mice, modeling neural tube defects (NTDs), possess a gain-of-function mutation in Lrp6, a key co-receptor in WNT signaling.
• Dietary folic acid (FA) is known to prevent NTDs, but its direct impact on LRP6 function and associated developmental defects remained unclear.

Purpose of the Study:

• To investigate the direct influence of folic acid (FA) on LRP6 function and its role in neural tube defect (NTD) development in Lrp6-deficient embryos.
• To elucidate the molecular mechanisms underlying the interaction between LRP6 deficiency, FA supplementation, and embryonic development.

Main Methods:

• Prenatal folic acid (FA) supplementation was administered to LRP6-deficient embryos and controls.
• Analysis included assessment of embryonic lethality, NTD occurrence, cell proliferation, WNT signaling activity (using a TCF/LEF-reporter transgene), and gene expression profiling.

Main Results:

• Enriched FA diets reduced overall birth defects but increased early lethality in Lrp6(-/-) embryos and exacerbated NTDs in surviving nulls.
• FA supplementation enhanced proliferation in wild-type neuroepithelia but not in mutants, and attenuated LRP5/6-dependent WNT signaling in cell culture.
• Gene expression analysis revealed significant interactions between Lrp6 deficiency and FA, particularly in pathways regulating mitochondrial function, metabolism, WNT signaling, and cytoskeletal dynamics.

Conclusions:

• FA supplementation may rescue certain fetal defects by normalizing hyperactive WNT signaling in conditions like the Lrp6(Cd/Cd) mutation.
• Conversely, in LRP6-deficient embryos, elevated FA further attenuates already reduced WNT activity, compromising neurodevelopment and increasing NTD severity.