title: LRP2 mediates folate uptake in the developing neural tube.
abstract: The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure.
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Kur
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Mecklenburg
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany hammes@mdc-berlin.de.
authors.forename: Annette
authors.initials: A
authors.lastname: Hammes
mesh_terms: D000818:Animals; D004705:Endocytosis; D058975:Folate Receptor 1 / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C113607:Alx3 protein, mouse; D058975:Folate Receptor 1; C520574:Folr1 protein, mouse; D018398:Homeodomain Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D058978:Reduced Folate Carrier Protein; C548700:Slc19a1 protein, mouse; D005492:Folic Acid
keywords: Embryonic development; Endocytic receptor; Folate; Folate receptor; LRP2; Neural tube closure defects