Yolk Sac MicroRNAs Regulate Brain Development

卵黄囊 MicroRNA 调节大脑发育

• 批准号: 10750884
• 负责人: Rachel Anne Keuls
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2025-08-16
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750884
• 关键词: Ablation; Address; Attention Deficit Disorder; Bilateral; Biological Assay; Birth; Blood Cells; Brain; CD 200; Cell Separation; Cell surface; Cells; Cephalic; Coculture Techniques; Data; Defect; Development; Differentiated Gene; Disease; Dyslipidemias; Embryo; Endoderm; Event; Failure; Fatty Acids; Fetus; Flow Cytometry; Folic Acid Antagonists; Folic Acid Deficiency; Glucose; Goals; Growth; Harvest; Heme; Human; Hyperglycemia; Image; Intellectual functioning disability; Link; Lipids; Luciferases; Maternal-Fetal Exchange; Measures; Mesoderm; Metabolic; Metabolism; MicroRNAs; Morphogenesis; Mus; Neural Tube Closure; Neural Tube Development; Neural tube; Neurodevelopmental Disorder; Neuroepithelial; Neuroepithelial Cells; Neurologic; Neuronal Differentiation; Neurons; Nutrient; PDGFRA gene; Pathway interactions; Phagocytosis; Phenotype; Placenta; Pregnancy; Prevalence; Prevention; Process; Quality of life; Role; SOX1 gene; Scanning Electron Microscopy; Structural defect; Tamoxifen; Tissues; Tomatoes; Transmission Electron Microscopy; Unhealthy Diet; United States; Visceral; WNT Signaling Pathway; Work; Yolk Sac; absorption; autism spectrum disorder; cell motility; cellular microvillus; cranium; disability; dopaminergic neuron; experience; fetal; in utero; maternal hyperglycemia; metabolomics; mind control; nerve stem cell; neuroepithelium; neurogenesis; neuroregulation; novel strategies; novel therapeutic intervention; nutrient absorption; prevent; recruit; spatiotemporal; transcriptome sequencing; uptake

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.

项目摘要/摘要 仅在美国，每年就有60多万婴儿出生， 包括自闭症谱系障碍、注意力缺陷、 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往往发生在大脑发育之前。 怀孕被发现。大脑发育的第一步，大脑的两侧半球 神经上皮汇聚形成神经管，是一个快速形态发生的时期， 代谢需求增加。神经管对母体代谢的变化很敏感 和疾病状态，如母亲高血糖症和叶酸缺乏症， 神经性残疾神经管关闭发生在胎盘建立之前， 被卵黄囊吸收和处理。如何进行母胎营养交换 在神经管闭合过程中的调节还没有很好的理解。卵黄囊也产生细胞， 迁移到早期脑中以控制神经管闭合期间的神经元分化。是 对卵黄囊来源的细胞如何调节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，这表明它在母体发育中起作用。 胎儿营养交换microRNA是否调节母胎营养交换 卵黄囊仍然未知。我们发现，miR-290在卵黄囊中稳健表达， 高血糖妊娠中miR-290的内胚层和丢失导致神经管衰竭 结束此外，我们发现表达miR-290的卵黄囊来源的血细胞在基底膜， 神经上皮在miR-290缺失后，我们发现在小鼠中卵黄囊来源的血细胞减少， 胚胎颅区和神经发生的显着减少。我们假设miR- 290调节跨卵黄囊的母胎营养交换，并且卵黄囊来源的 血细胞是神经上皮正常发育所必需的。拟议的工作将揭示 卵黄囊和发育中的胚胎之间的相互作用如何促进大脑发育 对预防智力残疾至关重要。本研究的主要目的是确定 miR-290在神经管闭合过程中如何调节卵黄囊的发育和功能， 确定卵黄囊衍生细胞如何调节神经上皮发育。了解如何 卵黄囊控制着神经管的闭合，早期的大脑发育将呈现出新的 预防神经发育障碍的治疗方法。