Microarray analysis of E9.5 reduced folate carrier (RFC1; Slc19a1) knockout embryos reveals altered expression of genes in the cubilin-megalin multiligand endocytic receptor complex

Abstract

Background: The reduced folate carrier (RFC1) is an integral membrane protein and facilitative anion exchanger that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. Adequate maternal-fetal transport of folate is necessary for normal embryogenesis. Targeted inactivation of the murine RFC1 gene results in post-implantation embryolethality, but daily folic acid supplementation of pregnant dams prolongs survival of homozygous embryos until mid-gestation. At E10.5 RFC1 -/-embryos are developmentally delayed relative to wildtype littermates, have multiple malformations, including neural tube defects, and die due to failure of chorioallantoic fusion. The mesoderm is sparse and disorganized, and there is a marked absence of erythrocytes in yolk sac blood islands. The identification of alterations in gene expression and signaling pathways involved in the observed dysmorphology following inactivation of RFC1-mediated folate transport are the focus of this investigation.

Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes

“…54 Targeted inactivation of the reduced folate carrier, which facilitates folate delivery into cells, results in embryonic lethality at E10.5 due to neural and hematopoietic defects, 55 and components of the Megalin complex are among the most significantly disrupted genes in null embryos. 38 Coordinated upregulation of a receptor that facilitates folate uptake in HECs would be consistent with demand for an essential hematinic in cells that are on the threshold of a replicative phase.…”

“…Lrp2/Megalin is a member of an endocytic receptor complex that is involved in maternal-fetal transport of folate and other nutrients, lipids, and morphogens such as sonic hedgehog (Shh) and retinoids. 38 Given these associations, we postulated that Lrp2 upregulation in blood precursors was likely to be of functional significance.…”

Mono-2-ethylhexyl phthalate (MEHP) alters histiotrophic nutrition pathways and epigenetic processes in the developing conceptus

“…The MERC is responsible for the uptake of a vast array of nutrients and is also a major transporter of the developmental ligands crucial for neurulation such as Sonic Hedgehog (Shh) and retinoic acid [10, 53–59]. Vitamin B 12 and folate are also co-transported across epithelia via the MERC by carrier proteins, suggesting a link between methyl donor metabolism and the MERC [9, 10]. Solute carrier (SLC) families of transporters are also crucial for the transport of nutrients across membranes, including choline, betaine, folate, and amino acids required for C 1 metabolism.…”

Analysis of the expression pattern of the carrier protein transthyretin and its receptor megalin in the human scalp skin and hair follicles: hair cycle-associated changes

“…It is involved in transepithelial transport and cellular uptake of vitamins A and E, and thyroxine, by binding with TTR-RBP and thyroxine-binding protein (9200) complexes (Christensen et al 1999;Monaco 2000;Raghu and Sivakumar 2004), which are essential for keratinocyte proliferation and differentiation (Huang and Vieira 2006) and promote hair growth (Bazzano et al 1993;Yoo et al 2007). MEG also mediates cellular uptake of vitamins B 12 (cobalamin) (Moestrup et al 1996) and folate (Birn 2006;Gelineau-van Waes et al 2008), which act as co-enzymes and contribute in the biosynthesis of purines, pyrimidines, and certain amino acids that are necessary for cell survival and proliferation (Gelineau-van Waes et al 2008). It is a Ca 2?…”

“…MEG is an endocytic multi-ligand receptor and is involved in the cellular uptake of many biomolecules other than vitamin A and thyroxine. It mediates the uptake of vitamin E (Lundgren et al 1997), vitamins B 12 (Moestrup et al 1996), folate (Birn 2006;Gelineau-van Waes et al 2008), and vitamin D via interacting with vitamin D receptor (Ellison et al 2007), which are collectively essential for keratinocyte proliferation and differentiation, and promote hair growth. Vitamin D receptor knockout mice had defects in hair follicle cycling and keratinocyte proliferation leading to epidermal thickening, dermal cyst formation, and alopecia (Ellison et al 2007).…”