The role of megalin (LRP-2/Gp330) during development

Abstract

Megalin (LRP-2/GP330), a member of the LDL receptor family, is an endocytic receptor expressed mainly in polarised epithelial cells. Identified as the pathogenic autoantigen of Heymann nephritis in rats, its functions have been studied in greatest detail in adult mammalian kidney, but there is increasing recognition of its involvement in embryonic development. The megalin homologue LRP-1 is essential for growth and development in Caenorhabditis elegans and megalin plays a role in CNS development in zebrafish. There is now also evidence for a homologue in Drosophila. However, most research concerns mammalian embryogenesis; it is widely accepted to be important during forebrain development and the developing renal proximal tubule. Megalin is also expressed in lung, eye, intestine, uterus, oviduct, and male reproductive tract. It is found in yolk sacs and the outer cells of pre-implantation mouse embryos, where interactions with cubilin result in nutrient endocytosis, and it may be important during implantation. Models for megalin interaction(s) with Sonic Hedgehog (Shh) have been proposed. The importance of Shh signalling during embryogenesis is well established; how and when megalin interacts with Shh is becoming a pertinent question in developmental biology.

The Developing Chicken Yolk Sac Acquires Nutrient Transport Competence by an Orchestrated Differentiation Process of Its Endodermal Epithelial Cells

“…This triad has been established as a key player in nutrient transport by the mammalian visceral YS (1,26). Mutations in any of the three genes or blocking of their function by antibodies compromises normal embryonic development in rodents, especially affecting neural tube and brain formation (29,42). The ligand binding domains of cubilin and LRP2 recognize a vast number of diverse proteins, many of which are yolk constituents, such as protein-bound vitamins, hormones, and a range of lipoproteins (28).…”

Deficits in receptor-mediated endocytosis and recycling in cells from mice bearing a disruption of the Gpr107 locus

“…Previous data have shown that the multi-ligand endocytic receptors cubilin and megalin exert their roles in the visceral epithelial cells of the embryonic yolk sac, intestine, kidney and thyroid gland and participate in the transportation of vitamins B12 and D3, lipid-binding proteins, poorly water soluble hormones and their binding proteins, mineral-binding proteins and a variety of heterogeneous ligands (Kaseda et al, 2011;Kozyraki et al, 1999;Kozyraki et al, 2001;Nykjaer et al, 2001;Christensen and Birn, 2002;Christensen and Verroust, 2002;Fisher and Howie, 2006;Kozyraki and Gofflot, 2007). Because cubilin mediates nutrient transport from the maternal to the fetal circulation, the loss or partial incapacitation of cubilin and megalin function could be expected to jeopardize fetal development.…”

“…The reduced abundance of cubilin transcripts was validated by quantitative real-time (RT)-PCR in multiple embryos and yolk sacs (supplementary material Fig. S1 (Kozyraki et al, 1999;Kozyraki et al, 2001;Nykjaer et al, 2001;Assémat et al, 2005;Kozyraki and Gofflot, 2007), as well as the transport of lipids and morphogens, such as sonic hedgehog (Shh), and retinoids (supplementary material Table S3), that play crucial roles in normal embryogenesis (Kozyraki et al, 1999;Willnow et al, 1999;Fisher and Howie, 2006;Kozyraki and Gofflot, 2007).…”

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

“…In the adult, megalin expression is restricted in the central nervous system (CNS) to the choroid plexus (Chun et al, 1999;Carro et al, 2005), the ependymal cells of the lateral ventricles (Gajera et al, 2010) and in spinal cord (Wicher et al, 2006). Megalin expression has been reported in the sensory organs, such as the inner ear (Mizuta et al, 1999;Konig et al, 2008) and the eye (Lundgren et al, 1997;Assemat et al, 2005a;Fisher and Howie, 2006). The presence of megalin has been also found in non-epithelial cells, such as a subpopulation of neural progenitors in the embryonic mouse spinal cord (Wicher et al, 2005), oligodendrocytes of the mouse spinal cord (Wicher et al, 2006), retinal ganglion cells (Fitzgerald et al, 2007) and cerebellar granule neurons (Ambjorn et al, 2008).…”