Yolk Sac MicroRNAs Regulate Brain Development

项目摘要/摘要 仅在美国，每年就有超过60万名婴儿出生，这些婴儿将继续遭受 来自神经发育障碍，包括自闭症谱系障碍，注意力缺陷 精神障碍和其他智力残疾。预防和治疗的主要障碍 神经发育障碍是大脑发育的第一步通常发生在 怀孕被发现了。大脑发育的第一步，在这一步中，大脑的两侧半部分 神经上皮细胞汇聚形成神经管，是一个快速形态发生的时期 新陈代谢需求增加。神经管对母体新陈代谢的变化很敏感 母亲高血糖和叶酸缺乏等疾病状态与 神经性残疾。神经管关闭发生在胎盘建立和营养物质建立之前 取而代之的是被卵黄囊吸收和处理。母婴营养交换是如何进行的 在神经管关闭过程中的调节还不是很清楚。卵黄囊也会产生细胞， 在神经管关闭期间迁移到早期大脑以控制神经元分化。它是 人们对卵黄囊来源的细胞如何调控神经上皮的发育知之甚少。 卵黄囊中的microRNA功能对胚胎生长至关重要，这表明在母体发育过程中发挥了作用。 胎儿营养交换。MicroRNAs是否调节母婴营养交换 卵黄囊仍然是未知的。我们发现miR-290在卵黄囊中强势表达。 高血糖妊娠中内胚层和miR-290的丢失导致神经管失败 结案了。此外，我们发现miR-290在基底部表达卵黄囊来源的血细胞。 神经上皮细胞。在miR-290缺失后，我们发现卵黄囊来源的血细胞在 胚胎颅区和神经发生明显减少。我们假设MIR- 290调节跨卵黄囊和卵黄囊来源的母胎营养交换 血细胞是神经上皮细胞正常发育所必需的。拟议中的工作将揭示 卵黄囊和发育中胚胎之间的相互作用如何促进大脑发育 对于预防智力残疾将是至关重要的。这项研究的主要目标是确定 MiR-290在神经管闭合和卵黄囊发育和功能中的调节作用 确定卵黄囊来源的细胞如何调控神经上皮细胞发育。了解如何 卵黄囊控制神经管闭合和早期大脑发育将呈现一种新的 预防神经发育障碍的治疗方法。

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.