Mechanisms of folate action during nervous system development

University Of California At Davis, Davis CA

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Abstract

Abstract Supplementation with the vitamin B9, folate, during pregnancy reduces the incidence of neural tube defects (NTDs), one of the most common and serious birth defects diagnosed in human fetuses and newborns. NTDs result from the failure of neural tube closure during early fetal development, which potentially exposes the neural tissue to a toxic environment and mechanical trauma, resulting in neural tissue degeneration and severe neurological consequences, including fetus and newborn death. Under the previous funding period we made a paradigm-shifting discovery, that the rescue by folate of folate receptor 1 (FOLR1) deficiency-induced NTD phenotype in Xenopus laevis embryos and in human induced pluripotent stem cell (hiPSC)-derived neural organoids is independent of folate participation in metabolism. Instead, we find that FOLR1 regulates apical endocytosis and adherens junction molecule turnover by counteracting the action of the interacting protein CD2- Associated Protein (CD2AP), that we discovered through interactomic studies. The concerted actions of both FOLR1 and CD2AP are important for neural plate cell apical constriction and neural plate folding. The molecular signature of the signaling pathway recruited by folate/FOLR1 during neural tube formation demands further investigation. We will follow up on the discoveries from our previous investigation and preliminary results by interrogating the signaling partners and mechanisms underlying folate/FOLR1 action through candidate and unbiased screening approaches. We will focus on folate/FOLR1 regulation of Ca2+ dynamics in the neural plate during folding. We will investigate the potential interaction between FOLR1, and prohibitins, a family of scaffold proteins that serve as signaling hubs, by discovering their role in regulating apical endocytosis and adherens junction remodeling by using Xenopus laevis embryos and hiPSC-derived neural organoids as model systems. Identifying the signaling mechanisms that mediate folate/FOLR1 action during neural tube formation may contribute to defining risk groups and treatment of folate insensitive and sensitive NTDs, as well as potential unintended consequences of folate supplementation. In addition, the findings resulting from this investigation will contribute to other fields of research including cancer, neurodegenerative diseases, neurogenesis and neuronal differentiation, to name a few, given the prominence of signaling molecules being studied and the potential for identifying further novel interactors of these molecules.