Prevention of neural tube defects in Lrp2 mutant mouse embryos by folic acid supplementation

Abstract

Background Neural tube defects (NTDs) are among the most common structural birth defects in humans and are caused by the complex interaction of genetic and environmental factors. Periconceptional supplementation with folic acid can prevent NTDs in both mouse models and human populations. A better understanding of how genes and environment interact is critical towards development of rational strategies to prevent NTDs. Low density lipoprotein-related protein 2 (Lrp2) is involved in endocytosis of the folic acid receptor among numerous other nutrients and ligands. Methods We determined the effect of iron and/or folic acid supplementation on the penetrance of NTDs in the Lrp2null mouse model. The effects of supplementation on folate and iron status were measured in embryos and dams. Results Periconceptional dietary supplementation with folic acid did not prevent NTDs in Lrp2 mutant embryos whereas high levels of folic acid supplementation by intraperitoneal injection did. Importantly, Lrp2null/+ dams had reduced blood folate levels that improved with daily intraperitoneal injections of folate but not dietary supplementation. On the contrary, iron supplementation had no effect on the penetrance of NTDs in Lrp2 mutant embryos and negated the preventative effect of folic acid supplementation in Lrp2null/null mutants. Conclusions Lrp2 is required for folate homeostasis in heterozygous dams and high levels of supplementation prevent NTDs. Furthermore, high levels of dietary iron supplementation interfered with folic acid supplementation negating the positive effects of supplementation in this model.

Insights into the Etiology of Mammalian Neural Tube Closure Defects from Developmental, Genetic and Evolutionary Studies

“…A functionally related gene that also causes exencephaly in mice is Lrp2 , a multi-ligand membrane receptor that seems to mediate uptake of folic acid into cells by Folr1 at the apical surface of the developing neuroepithelium [ 211 ]. Maternal injection with folic acid during early gestation reduces the NTD frequency in Lrp2 mutants by half; dietary supplementation with folic acid is not effective [ 212 ].…”

Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds

“…Most of the clinical characteristics seen in patients with LRP2 gene mutations are also present in the LRP2-deficient mouse models (Cases et al, 2015;Hammes et al, 2005;Kur et al, 2014;Sabatino et al, 2017;Spoelgen et al, 2005;Wicher and Aldskogius, 2008). Our report demonstrates that Xenopus is a new valuable model for the functional analysis of Lrp2 deficiency.…”

“…Interestingly, LRP2-deficient mice not only suffer from HPE caused by ventral forebrain defects, but also display defects of the anterior dorsolateral neural tube as well as spinal cord anomalies that cannot be explained by loss of SHH signaling in the developing forebrain (Kur et al, 2014;Wicher and Aldskogius, 2008;Ybot-Gonzalez et al, 2002). In previous studies, we and other labs demonstrated that LRP2 null mutants present with a dilated dorsal neural tube and in 38 % of all mice we observed cranial neural tube closure defects (NTDs; Kur et al, 2014;Sabatino et al, 2017). Of note, human LRP2 variants have now also been identified in patients suffering from NTDs, ultimately leading to anencephaly and myelomeningocele (open spina bifida;…”

Identification of novel disease relevant genetic modifiers affecting the SHH pathway in the developing brain

“…Lrp2 −/− mutant mice studied on a C57BL/6N, a mixed C57BL/6N; 129/SvEMS-Ter, CD1, and a C3H/HeNcrl background show fully penetrant forebrain defects and perinatal lethality (Sabatino et al, 2017; Spoelgen et al, 2005; Willnow et al, 1996). We and others previously found that a Lrp2 267/267 ENU mutant line on a predominantly FVB/N background survived to adulthood (Gajera et al, 2010; Zarbalis et al, 2004; Zywitza et al, 2018).…”