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.
Highlights
The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2), known as megalin (Saito et al, 1994), is a multifunctional cell-surface receptor that is structurally related to the LDL receptor (Nykjaer and Willnow, 2002)
Closure of the rostral neural tube is impaired in LRP2deficient mouse embryos We systematically examined the neural tube closure phenotype of Lrp22/2 mice and Shh-null mutant mice
Over the past years it became well accepted that members of the LDL receptor family, including LRP2, play an important role in signaling during embryonic development
Summary
The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2), known as megalin (Saito et al, 1994), is a multifunctional cell-surface receptor that is structurally related to the LDL receptor (Nykjaer and Willnow, 2002). Examples are the re-uptake of vitamin D and retinol from the primary urine (Christensen et al, 1999; Nykjaer et al, 1999), as well as the uptake of androgens and estrogens into steroid-responsive cells (Hammes et al, 2005). The receptor is highly expressed in the neuroepithelium and loss of receptor activity in the developing central nervous system (CNS) in gene-targeted mice causes holoprosencephaly (HPE), a failure of the forebrain hemispheres to separate along the midline (Spoelgen et al, 2005; Willnow et al, 1996).
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