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:
    9898491
  • 负责人:
  • 金额:
    $ 48.15万
  • 依托单位:
  • 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

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/文摘

项目成果

期刊论文数量(0)
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Chengji Zhou其他文献

Chengji Zhou的其他文献

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{{ truncateString('Chengji Zhou', 18)}}的其他基金

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
  • 批准号:
    10377371
  • 财政年份:
    2018
  • 资助金额:
    $ 48.15万
  • 项目类别:
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
  • 批准号:
    10115140
  • 财政年份:
    2018
  • 资助金额:
    $ 48.15万
  • 项目类别:
Cellular and molecular mechanisms of orofacial clefts
口面裂的细胞和分子机制
  • 批准号:
    9382180
  • 财政年份:
    2017
  • 资助金额:
    $ 48.15万
  • 项目类别:
Cellular and molecular mechanisms of orofacial clefts
口面裂的细胞和分子机制
  • 批准号:
    10198899
  • 财政年份:
    2017
  • 资助金额:
    $ 48.15万
  • 项目类别:
Cellular and molecular mechanisms of orofacial clefts
口面裂的细胞和分子机制
  • 批准号:
    9511784
  • 财政年份:
    2017
  • 资助金额:
    $ 48.15万
  • 项目类别:
Wnt Signaling in Craniofacial Developmental Disorders
颅面发育障碍中的 Wnt 信号转导
  • 批准号:
    8450649
  • 财政年份:
    2011
  • 资助金额:
    $ 48.15万
  • 项目类别:
Wnt Signaling in Craniofacial Developmental Disorders
颅面发育障碍中的 Wnt 信号转导
  • 批准号:
    8083275
  • 财政年份:
    2011
  • 资助金额:
    $ 48.15万
  • 项目类别:
Wnt Signaling in Craniofacial Developmental Disorders
颅面发育障碍中的 Wnt 信号转导
  • 批准号:
    8236888
  • 财政年份:
    2011
  • 资助金额:
    $ 48.15万
  • 项目类别:
Wnt Signaling in Craniofacial Developmental Disorders
颅面发育障碍中的 Wnt 信号转导
  • 批准号:
    8643094
  • 财政年份:
    2011
  • 资助金额:
    $ 48.15万
  • 项目类别:

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