Yolk Sac MicroRNAs Regulate Brain Development

项目总结/文摘

PROJECT SUMMARY/ABSTRACT In the United States alone, over 600,00 babies are born each year that will go on to suffer from a neurodevelopmental disorder including autism spectrum disorders, attention deficit disorder, and other intellectual disabilities. A major obstacle to preventing and treating neurodevelopmental disorders is that the first steps of brain development occur often before the pregnancy is discovered. The first step of brain development, in which the bilateral halves of the neuroepithelium converge to form the neural tube, is a period of rapid morphogenesis that creates heightened metabolic demand. The neural tube is sensitive to changes in maternal metabolism and disease states such as maternal hyperglycemia and folate deficiency have been linked to neurological disability. Neural tube closure occurs before the placenta is established and nutrients are instead absorbed and processed by the yolk sac. How maternal-fetal nutrient exchange is regulated during neural tube closure is not well understood. The yolk sac also generates cells that migrate into the early brain to control neuronal differentiation during neural tube closure. It is poorly understood how yolk sac-derived cells regulate development of the neuroepithelium. MicroRNA function in the yolk sac is critical for embryonic growth, suggesting a role in maternal- fetal nutrient exchange. Whether microRNAs regulate maternal-fetal nutrient exchange across the yolk sac remains unknown. We find that miR-290 is robustly expressed in the yolk sac endoderm and loss of miR-290 in hyperglycemic pregnancies results in a failure of neural tube closure. Further, we find miR-290 expressing yolk sac-derived blood cells at the basal neuroepithelium. Upon miR-290 deletion we find a reduction in yolk sac-derived blood cells in the embryonic cranial region and a significant reduction of neurogenesis. We hypothesize that miR- 290 regulates maternal-fetal nutrient exchange across the yolk sac and that yolk sac-derived blood cells are required for proper neuroepithelial development. The proposed work will uncover how the interaction between the yolk sac and developing embryo facilitates brain development and will be critical for preventing intellectual disability. The major goals of this study are to identify how miR-290 regulates development and function of the yolk sac during neural tube closure and determine how yolk sac-derived cells regulate neuroepithelial development. Understanding how the yolk sac controls neural tube closure and early brain development will present a new therapeutic approach to prevent neurodevelopmental disorders.