Maternofetal transport of vitamin B₁₂: role of TCblR/CD320and megalin

Abstract

Vitamin B deficiency causes megaloblastic anemia and neurologic disorder in humans. Gene defects of transcobalamin (TC) and the transcobalamin receptor (TCblR), needed for cellular uptake of the TC-bound B, do not confer embryonic lethality. TC deficiency can produce the hematologic and neurologic complications after birth, whereas TCblR/ gene defects appear to produce mild metabolic changes. Alternate maternofetal transport mechanisms appear to provide adequate B to the fetus. To understand this mechanism, we evaluated the role of TC, TCblR/, and megalin in maternofetal transport of B in a TCblR/-knockout (KO) mouse. Our results showed high expression of TCblR/ in the labyrinth of the placenta, embryonic brain, and spinal column in wild-type (WT) mice. Megalin expression was about the same in both WT and KO mouse visceral yolk sac, brain, and spinal column. Megalin mRNA was down-regulated in the KO embryonic spinal cord (SC) and kidneys. Megalin expression remained unaltered in adult WT and KO mouse brain, SC, and kidneys. Injected dsRed-TC-B and TC-CoB accumulated in the visceral yolk sac of KO mice where megalin is expressed and provides an alternate mechanism for the maternofetal transport of Cbl during fetal development.-Arora, K., Sequeira, J. M., Quadros, E. V. Maternofetal transport of vitamin B: role of TCblR/ and megalin.

Transcellular transport of cobalamin in aortic endothelial cells

“…Under our experimental conditions, Ds-RED-holo-TC segregated to the surface of the cell and underwent internalization within 2 h (Fig. 1C), as previously documented in other cell types (15,46). Immunodetection of CD320 receptor indicated low levels of soluble CD320 in the conditioned culture medium and substantial amounts of the receptor in whole-cell extracts of BAECs (Supplemental Fig.…”

“…Endocytosis and transcytosis of holo-TC have also been proposed as important mechanisms for the mobilization of maternal Cbl in the placenta (42)(43)(44)(45). Investigation of maternofetal Cbl transfer in a CD320 knockout mouse model showed that, in the absence of a functional CD320 receptor, Cbl could be supplied to the fetus by uptake of holo-TC by megalin, a multiligand receptor (46).…”

Imaging Cobalamin Uptake within Malignant Breast Tumors In Vivo

“…The importance of these receptors in supporting cellular proliferation was emphasized when antibodies directed against MEG and CUBAM, but not TC-R, caused fetal demise after their injection into pregnant mice [35]. Correspondingly, murine TC-R knock-out fetuses survived only until birth due to MEG maintaining maternofetal transport of Cbl in the visceral yolk sac and therefore Cbl uptake within fetal brain, spinal cord, and renal tissue in utero [36].…”

Neuropathology of vitamin B12deficiency in theCd320−/−mouse

“…of Cd320 2/2 mice corrected some of the hematologic parameters, such as HGB, HCT, and RDW but did not correct or worsen the neuropathology. Although, the levels of Cbl in the Cd320 2/2 mouse liver and spleen were lower, they were not as severely depleted as in the brain and SC, suggesting an alternate pathway for Cbl uptake in these organs if additional Cbl is available through diet (23,24). Furthermore, lack of Cbl uptake in the CNS of the Cd320 2/2 mouse fed a normal diet contributes to elevated TC-Cbl in the blood and results in increased Cbl in the kidneys via uptake by megalin (3).…”

“…Six groups of C57BL/6J wild-type (Cd320 +/+ ) and TCblR/Cd320knockout (Cd320 2/2 ) [C57BL/6J-Cd320Gt(pGt01xft2)Qua] mice, 5-mo-old males and females (1:1 ratio), backcrossed twice on a C57BL/6J background, were used. The age of the mice for the study was based on the observation of severe CNS Cbl deficiency in the Cd320 2/2 mice and systemic Cbl deficiency after 3 mo of consuming a Cbl-deficient diet and the observation of behavioral deficits in 5-mo-old mice (23,24). The wild-type C57BL/6J mice (Cd320 +/+ ) used in the study were derived from a wild-type litter, and the Cd320 2/2 were generated by breeding homozygous mice.…”