Contribution of the sacral neural crest to the peripheral nervous system of the post-umbilical gastrointestinal tract

骶神经嵴对脐后胃肠道周围神经系统的贡献

基本信息

  • 批准号:
    10644256
  • 负责人:
  • 金额:
    $ 55.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

The enteric nervous system (ENS), the largest portion of the peripheral nervous system, is derived from neural crest populations referred to as “vagal” and “sacral”, arising from the neck and tail regions, respectively. However, much less has been published about sacral than vagal neural crest. To rectify this knowledge gap, we propose to: 1. characterize the temporal sequence of migration and differentiation of sacral neural crest cells into neuronal subtypes in the hindgut; 2. transcriptionally profile the sacral neural crest as at multiple time points and compare with that of vagal neural crest; 3. test function of transcription factors that may drive sacral neural crest cell fate choice. The results will enable us to test whether vagal and sacral neural crest cells give rise to similar or distinct types of enteric neurons and elucidate the influence of the intestinal environment on their differentiation. We will characterize the chick sacral neural crest using a novel lineage labeling technique of Replication Incompetent Avian (RIA) retroviruses that enables us to specifically target and isolate by FACS the sacral neural crest-derived population to perform the following aims: Specific Aim 1: Retrovirus-mediated lineage analysis of the chick sacral compared with vagal neural crest: We will label the neural tube caudal to somite 27 with RIA retroviruses that permanently label sacral neural crest cells in order to follow their long term fate. Preliminary results suggest that sacral neural crest-derived cells populate the post-umbilical gut and differentiate into cholinergic motor neurons as well as tyrosine hydroxylase positive cells. Sacral neural crest will be compared with vagal neural crest and interactions between the two populations examined. Finally, clonal relationships between sacral crest cells will be characterized. Specific Aim 2: Single cell RNA-seq of sacral neural crest-derived cells in the post-umbilical gut. To elucidate gene regulatory programs controlling progressive differentiation of sacral neural crest cells into neurons and glia in the hindgut, we propose to characterize the transcriptional profile of sacral crest-derived cells FACS sorted from the post-umbilical gut and processed by single cell (sc) RNA-seq at embryonic days (E) 2.5, E6, E8, 10, 15, 21 (prehatching); these will be compared with vagal crest-derived cells at comparable stages. Preliminary scRNA-seq data on E10 suggest that there are differences in neuronal subtypes produced by sacral vs vagal crest. scRNA-seq will enable us to sample different neuronal subtypes and infer developmental trajectories. Specific Aim 3: Role of transcriptional regulators into differentiation of sacral neural crest into neuronal and glial subtypes. Focusing on transcription factors that are present in the enteric precursor cluster (e.g. Nfatc1, Foxn2, Sox4, Sox21, Elf2, Znf536), we will test whether sacral neural crest-enriched transcription factors are critical for mediating proliferation, migration within the gut, and/or cell fate decisions. To this end, we will perform targeted loss of function in the sacral neural crest using a single-plasmid CRISPR-Cas9 strategy and examine subsequent effects on distribution and/or differentiation of sacral neural crest-derived cells.
肠神经系统(ENS)是周围神经系统的最大部分,来源于 神经嵴群称为“迷走神经”和“骶神经”,分别来自颈部和尾部区域。 然而,关于骶神经嵴的文献报道却比迷走神经嵴少得多。为了弥补这一知识差距, 我们建议:描述骶骨神经细胞迁移和分化的时间顺序 后肠嵴细胞分化为神经元亚型; 2.转录分析骶骨神经嵴, 多个时间点与迷走神经嵴比较; 3.转录因子功能检测 可能驱动骶骨神经嵴细胞的命运选择。结果将使我们能够测试迷走神经和骶神经 神经嵴细胞产生类似或不同类型的肠神经元,并阐明了神经嵴细胞对肠神经元的影响。 肠道环境对其分化的影响。我们将描述小鸡骶神经嵴使用一种新的 复制无能禽(RIA)逆转录病毒的谱系标记技术,使我们能够特异性地 通过流式细胞仪瞄准并分离骶骨神经嵴衍生群体,以实现以下目标: 特定目的1:鸡骶骨与迷走神经的逆转录病毒介导谱系分析 crest:我们将用RIA逆转录病毒标记第27体节尾侧的神经管, 以遵循它们的长期命运。初步结果表明,骶神经嵴来源的细胞 填充后脐肠并分化成胆碱能运动神经元以及酪氨酸羟化酶 阳性细胞将骶神经嵴与迷走神经嵴以及两者之间的相互作用进行比较 人口调查。最后,骶嵴细胞之间的克隆关系将被表征。 具体目标2:脐后肠中骶骨神经嵴衍生细胞的单细胞RNA-seq。到 阐明控制骶骨神经嵴细胞向神经元进行性分化的基因调控程序 和神经胶质细胞,我们建议用流式细胞仪来表征骶嵴衍生细胞的转录谱 从后脐肠中分选,并在胚胎日(E)2.5,E6,E8, 10、15、21(孵化前);这些将与可比较阶段的迷走嵴衍生细胞进行比较。初步 E10的scRNA-seq数据表明,骶神经与迷走神经产生的神经元亚型存在差异, 冠。scRNA-seq将使我们能够对不同的神经元亚型进行采样并推断发育轨迹。 具体目标3:转录调节因子在骶神经嵴分化为神经元中的作用 和神经胶质亚型。关注存在于肠前体簇中的转录因子(例如, Nfatc 1,Foxn 2,Sox 4,Sox 21,Elf 2,Znf 536),我们将测试是否骶神经嵴富集转录因子 对于介导增殖、肠内迁移和/或细胞命运决定至关重要。为此我们将 使用单质粒CRISPR-Cas9策略在骶神经嵴中进行靶向功能丧失, 检查对骶骨神经嵴衍生细胞的分布和/或分化的后续影响。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single-cell profiling coupled with lineage analysis reveals vagal and sacral neural crest contributions to the developing enteric nervous system.
  • DOI:
    10.7554/elife.79156
  • 发表时间:
    2023-10-25
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Jacobs-Li J;Tang W;Li C;Bronner ME
  • 通讯作者:
    Bronner ME
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Marianne Bronner其他文献

Marianne Bronner的其他文献

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{{ truncateString('Marianne Bronner', 18)}}的其他基金

Transcriptional regulation of neuronal cell lineage decisions in the developing enteric nervous system
发育中的肠神经系统神经细胞谱系决定的转录调控
  • 批准号:
    10444843
  • 财政年份:
    2022
  • 资助金额:
    $ 55.64万
  • 项目类别:
Transcriptional regulation of neuronal cell lineage decisions in the developing enteric nervous system
发育中的肠神经系统神经细胞谱系决定的转录调控
  • 批准号:
    10646306
  • 财政年份:
    2022
  • 资助金额:
    $ 55.64万
  • 项目类别:
Cell lineage and transcriptional analysis of the vertebrate neural plate border
脊椎动物神经板边界的细胞谱系和转录分析
  • 批准号:
    10178170
  • 财政年份:
    2020
  • 资助金额:
    $ 55.64万
  • 项目类别:
Progressive acquisition of novel neural crest derivatives along the neural axis during vertebrate evolution
脊椎动物进化过程中沿神经轴逐步获得新型神经嵴衍生物
  • 批准号:
    10397520
  • 财政年份:
    2019
  • 资助金额:
    $ 55.64万
  • 项目类别:
Clonal analysis of the cranial neural crest
颅神经嵴的克隆分析
  • 批准号:
    9929202
  • 财政年份:
    2019
  • 资助金额:
    $ 55.64万
  • 项目类别:
Progressive acquisition of novel neural crest derivatives along the neural axis during vertebrate evolution
脊椎动物进化过程中沿神经轴逐步获得新型神经嵴衍生物
  • 批准号:
    10617203
  • 财政年份:
    2019
  • 资助金额:
    $ 55.64万
  • 项目类别:
Clonal analysis of the cranial neural crest
颅神经嵴的克隆分析
  • 批准号:
    10312021
  • 财政年份:
    2018
  • 资助金额:
    $ 55.64万
  • 项目类别:
Cell lineage and transcriptional analysis of the vertebrate neural plate border
脊椎动物神经板边界的细胞谱系和转录分析
  • 批准号:
    10331009
  • 财政年份:
    2018
  • 资助金额:
    $ 55.64万
  • 项目类别:
Coupling gene regulatory and lineage analysis of the cardiac neural crest
心脏神经嵴的耦合基因调控和谱系分析
  • 批准号:
    10213819
  • 财政年份:
    2018
  • 资助金额:
    $ 55.64万
  • 项目类别:
Cell lineage and transcriptional analysis of the vertebrate neural plate border
脊椎动物神经板边界的细胞谱系和转录分析
  • 批准号:
    10549549
  • 财政年份:
    2018
  • 资助金额:
    $ 55.64万
  • 项目类别:

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