Heme as a determinant of brain development

Abstract

Metabolic support was long considered to be the only developmental function of haematopoiesis. In this role, erythroblast are considered simple carriers that transfer and deliver heme-bound diatomic oxygen to various developing organs. Herein, we report an unexpected function of erythroblasts that occur in a brief temporal window from embryonic day (E) 8.5-E9.5 by donation of sacrificial yolk sac erythroblasts to neuroepithelial cells of developing neural tube. In this temporal window, neuroepithelial cells transiently merge with endothelial lining of yolk sac blood vessels, gain access to the luminal contents and eventually engulf that luminal erythroblasts. Subsequently, neuroepithelial cells deplete the heme contents of cannibalised erythroblasts via process of trans-endocytosis. In consequence, cannibalistic neuroepithelial cells differentiate precociously into neurons. The complementary in vitro experiments revealed that access to exogenous heme can accelerate neuronal differentiation via enhanced availability of the key Wnt pathway mediator, catenin-β1, by redox-dependent mechanisms. The coupling of haematopoiesis and neurogenesis provides a fail-safe developmental mechanism that calibrates the energetic demands of developing neural tube to density of blood vessels and also to hematopietic activity. The molecular basis for reprogrammability of developmental time and the potency of heme as a temporal reprogrammer of development are discussed in separate chapters of the thesis. We anticipate that the mechanism disclosed herein may provide a basis to explain the long-established but unresolved causal association of neural tube defects and deficiency of hematopoietic micronutrients including folate.