Gene-Environment Interactions Resulting in Neural Tube Defects with 22q11 Deletions

基因-环境相互作用导致 22q11 缺失的神经管缺陷

• 批准号: 9536091
• 负责人: Irene E Zohn
• 金额: $ 21.51万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9536091
• 关键词: 22q11; 22q11 Deletion Syndrome; 3' Untranslated Regions; Affect; Benign; Binding; Biological; Biological Assay; Brain; Buffers; Cardiac development; Complex; Congenital Abnormality; Craniofacial Abnormalities; Data; Defect; Development; Disease; Dose; Embryo; Environmental Exposure; Environmental Risk Factor; Enzymes; Equilibrium; Exhibits; Feedback; Future; Gene Deletion; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Heart Abnormalities; Heterozygote; Human; In Situ Hybridization; Incidence; Individual; Intake; Live Birth; Luciferases; Mediating; MicroRNAs; Microprocessor; Mus; Neural Tube Closure; Neural Tube Defects; Neurologic Deficit; Neurons; Patients; Pattern; Penetrance; Phenotype; Play; Positioning Attribute; Pregnancy; Publishing; Reporting; Retinoic Acid-Binding Proteins; Risk; Role; Severities; Signal Transduction; Structural Congenital Anomalies; Syndrome; Testing; Transcript; Tretinoin; Variant; Vitamin A; Vitamin A Deficiency; base; craniofacial development; differential expression; experimental study; gene environment interaction; induced pluripotent stem cell; mouse model; mutant; novel; peripheral blood; postnatal; response

Project Summary/Abstract Vitamin A and its biologically active metabolite Retinoic Acid (RA) play critical roles in patterning the developing embryo. Vitamin A deficiency or excess can cause a variety of developmental abnormalities, including defects in craniofacial and cardiac development and neural tube closure (Neural Tube Defects, NTDs). Thus, RA levels and signaling must be tightly regulated for normal development to occur. The embryo accomplishes this by altering the expression of the RA buffering machinery (RA synthetic and degradation enzymes along with RA binding proteins) to buffer small alterations in environmental exposure. Expression of many microRNAs (miRNAs) are regulated by RA signaling and miRNAs target the RA buffering machinery. Thus miRNAs are well positioned to mediate the negative and positive feedback loops that constitute the RA buffering capacity of the embryo. Our published data demonstrate that the LgDel mouse model of DiGeorge/22q11 deletion syndrome (22q11DS) exhibits dysfunctional RA buffering capacity. This results in increased incidence of NTDs when challenged with normally benign alterations in RA exposures. 22q11DS is the most frequent gene deletion syndrome in humans affecting 1 in 4000 live births. Features of 22q11DS vary widely and are most commonly associated with cardiac and craniofacial defects; however, many cases of NTDs are reported in patients with 22q11 deletions. Dgcr8/Pasha, is an essential component of the microprocessor complex responsible for generating mature miRNAs and is located within the 22q11 deletion. While Dgcr8+/- embryos do not exhibit obvious embryonic phenotypes, multiple defects in neuronal function are described in postnatal mice. Importantly, neurological deficits are accompanied by altered expression of miRNAs in the brain of Dgcr8+/- mice and other mouse models of 22q11DS as well as altered miRNA expression in peripheral blood and induced pluripotent stem cells (iPSCs) from 22q11DS patients. Thus haploinsufficiency of Dgcr8 can have a critical impact on expression of mature miRNAs, possibly creating a bottleneck in miRNA processing. The majority of NTDs, cardiac and craniofacial defects are due to complex gene-environment interactions. Some environmental triggers contributing to NTDs are known, yet few genetic factors have been identified. Moreover, HOW environmental and genetic factors interact to cause NTDs remains largely undetermined. Our finding that the LgDel embryo has dysfunctional RA buffering capacity developing NTDs provides a novel opportunity to dissect the mechanisms by which gene-environment interactions might tip the balance to cause NTDs. In this proposal we will test the hypothesis that haploinsufficiency of Dgcr8 in the LgDel embryo results in a bottleneck in miRNA processing and dysfunctional RA buffering capacity.

项目总结/摘要 维生素A及其生物活性代谢产物视黄酸（RA）在形成维生素A的代谢过程中起着关键作用。 胚胎发育维生素A缺乏或过量可导致各种发育异常， 包括颅面和心脏发育缺陷以及神经管闭合（神经管缺陷， NTD）。因此，RA水平和信号传导必须严格调节才能正常发育。胚胎 通过改变RA缓冲机制（RA合成和降解）的表达来实现这一目标 酶沿着RA结合蛋白）以缓冲环境暴露中的微小变化。表达 许多微小RNA（miRNAs）受RA信号传导调节，并且miRNAs靶向RA缓冲机制。 因此，miRNAs很好地定位于介导构成RA的负反馈和正反馈环。 胚胎的缓冲能力。 我们已发表的数据表明DiGeorge/22 q11缺失综合征的LgDel小鼠模型 （22 q11 DS）表现出功能失调的RA缓冲能力。这导致NTD的发病率增加， 挑战RA暴露的正常良性变化。22 q11 DS是最常见的基因缺失 人类综合征影响1/4000活产婴儿。22 q11 DS的特征变化很大，最常见的是 与心脏和颅面缺陷相关;然而，许多NTD病例报告发生在 22 q11缺失。Dgcr 8/Pasha是微处理器复合体的重要组成部分，负责 产生成熟的miRNAs并位于22 q11缺失内。虽然Dgcr 8 +/-胚胎不表现出 在出生后的小鼠中描述了明显的胚胎表型、神经元功能的多种缺陷。 重要的是，神经功能缺损伴随着Dgcr 8 +/-小鼠脑中miRNA表达的改变。 小鼠和其他22 q11 DS小鼠模型以及外周血中改变的miRNA表达， 来自22 q11 DS患者的诱导多能干细胞（iPSC）。因此，Dgcr 8的单倍不足可以具有 对成熟miRNA的表达产生关键影响，可能在miRNA加工中产生瓶颈。 大多数NTD，心脏和颅面缺陷是由于复杂的基因-环境相互作用。 一些环境触发因素导致NTD是已知的，但很少有遗传因素已被确定。 此外，环境和遗传因素如何相互作用，导致NTD仍然在很大程度上不确定。我们 发现LgDel胚胎具有功能失调的RA缓冲能力，发展NTD提供了一种新的 有机会剖析基因-环境相互作用可能导致平衡的机制， NTD。在这个提议中，我们将检验LgDel胚胎中Dgcr 8的单倍不足的假设， 导致miRNA加工的瓶颈和RA缓冲能力的功能障碍。