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Surface ectodermal mechanism and maternal intervention of neural tube defects

神经管缺陷的表面外胚层机制及母体干预

基本信息

批准号：
10115140
负责人：
Chengji Zhou
金额：
$ 48.15万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115140
关键词：
Ablation Address Affect Anencephaly Animal Model Apical Biological Brain Cell Adhesion Cell Lineage Cell Polarity Cell physiology Cells Cephalic Child Congenital Abnormality Craniorachischises Defect Developed Countries Development Developmental Process Dietary Intervention Disease Dorsal Ectoderm Cell Embryo Exencephalies Exhibits F-Actin Folic Acid Food Future Gene Dosage Gene Targeting Genes Genetic Goals Human Image Inositol Intervention Knock-out Lead Mediating Molecular Mus Mutant Strains Mice Neural Fold Neural Tube Closure Neural Tube Defects Neural tube Neuroectoderm Neuroectodermal Cell Neuroepithelial Cells Newborn Infant Nutrient Pathway interactions Pharmacology Play Point Mutation Policies Prevention Regulation Research Resistance Resolution Risk Role Signal Pathway Signal Transduction Signaling Molecule Site Spinal Spinal Cord Spinal Dysraphism Structural Congenital Anomalies Supplementation Surface Surface Ectoderm Testing Therapeutic Translating Vertebral column WNT Signaling Pathway base beta catenin cell behavior clinical application constriction convergent extension disability early pregnancy experimental study folic acid supplementation fortification genetic manipulation genetic risk factor innovation insight loss of function maternal diabetes mother nutrition mouse model mutant mutant mouse model neonatal death neural plate neuroepithelium neuromechanism novel novel strategies planar cell polarity prevent programs rho GTP-Binding Proteins small molecule transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term goal of our research is to uncover the cellular and molecular mechanisms of mammalian neural tube closure defects. Understanding the basic mechanisms underlying neural tube closure may translate into applications for preventing neural tube closure defects, including exencephaly and anencephaly at the cranial region and spina bifida at the caudal spinal region. Craniorachischisis, the severest but rare neural tube closure defect with entirely open brain and spine, has been found in the animal model of planar cell polarity (PCP) signaling mutants. The Wnt/ß-catenin signaling pathway shares several components with the PCP signaling pathway, and plays crucial roles in a wide range of developmental processes and related disorders. However, the role of Wnt/ß-catenin signaling in neural tube closure and related structural birth defects remains poorly understood. Lrp6 is a coreceptor in the Wnt/ß-catenin signaling pathway and is also involved in the PCP signaling pathway with unknown mechanisms. Spontaneous point mutations in the Lrp6 gene give rise to either cranial or spinal neural tube closure defects in the mouse model, and are associated with neural tube closure defects in humans. Folate supplementation may not prevent neural tube closure defects in Lrp6 mutants. To address the role of Lrp6-mediated signaling cascades in neural tube closure, we have generated a conditional gene-targeting mouse line of Lrp6. Using various Cre mouse lines, we have preliminarily found that Lrp6 plays cell lineage- and region-specific roles in neural tube closure. On the other hand, Lrp6 may have functional redundancy with another coreceptor, Lrp5, in mediating ß-catenin signaling in neural tube closure. We have recently demonstrated that conditional ablation of ß-catenin in the neuroectodermal lineage cells causes spina bifida that is similar to, but severer than those seen in the neuroectodermal Lrp6 mutants, suggesting that Lrp5 may compensate for a partial loss-of-function of Lrp6 to mediate Wnt/ß-catenin signaling. Numerous studies have been focused on neuroectodermal or neuroepithelial cells that maybe important in neural plate folding or bending during neural tube closure. However, the role of the adjacent non-neural surface ectodermal cells during neural tube closure remains poorly understood. Based on our preliminary findings, we propose that Lrp5/6-mediated Wnt/ß-catenin signaling regulates a unique cellular process in the non-neural surface ectodermal cells to direct neural tube closure along the entire rostrocaudal body axis, and that disruption of the Wnt/ß-catenin signaling cascade in the non-neural surface ectodermal cells will cause a spectrum of all types of severe neural tube closure defects. We also propose that genetic activation of the key downstream effectors of Wnt/ß-catenin signaling can prevent neural tube closure defects in the surface ectodermal mutants. To address these hypotheses, we will conduct conditional gene- targeting analyses in combination with various powerful and innovative research approaches to examine the cellular and molecular mechanisms of neural tube closure defects in these novel mutant mouse models. We will also address the region-specific and gene-dosage-dependent roles of the Lrp5/6-mediated Wnt/ß-catenin signaling pathway during neural tube closure. We will test the genetic rescue of neural tube closure defects by conditional activation of the key candidate downstream effectors. This study may reveal significant clues towards preventing folate-untreatable neural tube closure defects in human newborns.

项目总结/摘要我们的长期研究目标是揭示哺乳动物细胞和分子机制，神经管闭合缺陷了解神经管闭合的基本机制，转化为预防神经管闭合缺陷的应用，包括露脑畸形和无脑畸形头部区域和尾部脊柱区域的脊柱裂。颅脊柱裂，最常见但罕见的在平面细胞的动物模型中发现了神经管闭合缺陷，具有完全开放的脑和脊柱极性（PCP）信号转导突变体。Wnt/β-catenin信号通路与Wnt/β-catenin信号通路共享几个组分。 PCP信号通路，并在广泛的发育过程中起着至关重要的作用，紊乱然而，Wnt/β-catenin信号在神经管闭合和相关结构出生中的作用，缺陷仍然知之甚少。Lrp 6是Wnt/β-连环蛋白信号通路中的共受体，并且也是Wnt/β-连环蛋白信号通路中的共受体。参与PCP信号通路，机制未知。Lrp 6的自发点突变在小鼠模型中，该基因引起颅或脊髓神经管闭合缺陷，并且与有神经管闭合缺陷的人叶酸补充剂可能无法防止神经管闭合 Lrp 6突变体的缺陷。为了阐明Lrp 6介导的信号级联在神经管闭合中的作用，我们已经产生了Lrp 6的条件基因靶向小鼠系。使用各种Cre鼠标线，我们有初步发现Lrp 6在神经管闭合中发挥细胞谱系和区域特异性作用。另另一方面，Lrp 6可能与另一个辅助受体Lrp 5在介导β-连环蛋白信号传导中具有功能冗余，神经管闭合我们最近已经证明，条件性切除β-连环蛋白在神经外胚层谱系细胞引起脊柱裂，与神经外胚层谱系细胞引起的脊柱裂相似，但比神经外胚层谱系细胞引起的脊柱裂更严重。神经外胚层Lrp 6突变体，表明Lrp 5可以补偿Lrp 6的部分功能丧失，介导Wnt/β-连环蛋白信号传导。大量的研究集中在神经外胚层或神经上皮这些细胞可能在神经管闭合过程中的神经板折叠或弯曲中起重要作用。然而，神经管闭合期间邻近的非神经表面外胚细胞仍然知之甚少。基于根据我们的初步发现，我们认为Lrp 5/6介导的Wnt/β-catenin信号调节了一种独特的非神经表面外胚层细胞中的细胞突起，以沿着整个神经管闭合喙尾体轴，以及非神经表面Wnt/β-连环蛋白信号级联的破坏外胚层细胞会引起一系列的所有类型的严重神经管闭合缺陷。我们亦建议 Wnt/β-catenin信号传导的关键下游效应物的遗传激活可以防止神经管闭合表面外胚层突变体的缺陷。为了解决这些假设，我们将进行条件基因- 目标分析结合各种强大且创新的研究方法来研究这些新的突变小鼠模型中神经管闭合缺陷的细胞和分子机制。我们还将阐述Lrp 5/6介导的Wnt/β-连环蛋白的区域特异性和基因剂量依赖性作用神经管闭合过程中的信号通路。我们将测试神经管闭合缺陷的基因拯救，关键候选下游效应物的有条件激活。这项研究可能会揭示重要的线索用于预防叶酸无法治疗的新生儿神经管闭合缺陷。