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; 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，每年有超过600,00名婴儿出生的婴儿 来自包括自闭症谱系障碍的神经发育障碍，注意力不足 疾病和其他智力残疾。防止和治疗的主要障碍 神经发育障碍是大脑发育的第一步经常发生在 发现怀孕。大脑发育的第一步，其中双侧的一半 神经上皮融合形成神经管，是一个快速形态发生的时期，会产生 代谢需求提高。神经管对孕妇代谢的变化敏感 以及诸如母体高血糖和叶酸缺乏等疾病状态与 神经疾病。神经管闭合发生在建立胎盘和营养之前 而是被蛋黄囊吸收和处理。产妇营养交换的方式 在神经管闭合期间的调节尚不清楚。蛋黄囊还会产生细胞 迁移到早期的大脑中，以控制神经管闭合期间的神经元分化。这是 鲜为人知的是蛋黄囊衍生的细胞如何调节神经上皮的发育。 蛋黄囊中的microRNA功能对于胚胎生长至关重要，表明在母体中起作用 胎儿养分交换。 microRNA是否调节跨性别的养分养分交换 蛋黄囊仍然未知。我们发现miR-290在蛋黄囊中表达了强烈的表达 内胚层和高血糖妊娠中miR-290的丧失导致神经管失败 关闭。此外，我们发现miR-290在基础上表达蛋黄囊衍生的血细胞 神经上皮。在miR-290缺失时，我们发现蛋黄囊衍生的血细胞的降低 胚胎颅区域和神经发生的显着降低。我们假设mir- 290调节蛋黄囊的产妇养分交换和蛋黄囊 需要血细胞才能进行适当的神经上皮发育。拟议的工作将发现 蛋黄囊和发育胚胎之间的相互作用如何促进大脑发育 并且对于预防智力残疾至关重要。这项研究的主要目标是确定 miR-290如何调节神经管闭合期间蛋黄囊的发展和功能 确定蛋黄囊衍生的细胞如何调节神经上皮发育。了解如何 蛋黄囊控制神经管闭合和早期大脑发育将提出新的 预防神经发育障碍的治疗方法。