Understanding the role of minor intron splicing in cortical development

了解小内含子剪接在皮质发育中的作用

基本信息

  • 批准号:
    10368061
  • 负责人:
  • 金额:
    $ 36.61万
  • 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:
    2018-03-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

Microcephaly is a devastating developmental defect that can be caused by inherited mutations such as those that inactivate the minor spliceosome or more recently Zika virus infections. In order to better understand the underlying molecular and cellular defects that cause microcephaly, we must first understand the molecular and cellular changes during normal development. The current proposal extends our finding that inactivation of the minor spliceosome in our U11 conditional knockout (cKO) mouse crossed with Emx1-Cre results in microcephaly observed at birth. We found that the primary cause of the microcephaly is loss of self-amplifying radial glial cells (RGCs) and delayed death of intermediate progenitor cells (IPCs) without the corresponding loss of neurons during early cortical development. Despite the complete loss of NPCs by E14, the developing mutant cortex managed to produce layer IV neurons that are normally born at/after E14. We found that this shift in neuron production is in conjunction with increased neurogenesis measured by EdU pulse/chase experiments. Based on these complex phenotypes, we have proposed three aims to test the hypothesis that minor spliceosome acts in a cell-type specific manner to inform cell cycle regulation, NPC competence, and neuron production. Experiments proposed in aim 1a are designed to elucidate the precise cell-cycle regulation of RGCs and IPCs and whether these two cell-types are undergoing self-amplifying or neurogenic cell divisions. In aim 1b, we explore how the changes in U11-null RGCs and IPCs impact neuron production. In aim 2, the objective is to understand the molecular underpinning of the cell-type specific effect of U11 loss. The one unique identifier of RGCs is that they divide rapidly compared to the IPCs, so the experiments proposed in aim 2a test the hypothesis that cell cycle speed confers susceptibility to loss of U11. Another possibility that the experiments proposed in aim 2b is that each cell-type has a unique signature of minor intron-containing genes (MIGs) that might make cells resistant/susceptible to U1 loss. Finally, RNAseq data showed activation of P53- medated apoptosis pathway and cell cycle defect in the U11-null tissue. The experiments proposed in aim 3a test whether rescuing cell cycle defect would prevent P53-mediated apoptosis or is P53-mediated apoptosis independent of the cell cycle defect. Aim 3b tests the idea that if P53 is ablation, would it rescue cell cycle or cell death and in turn rescue microcephaly. In all, we will find the role of this novel form of gene regulation in cortical development and in turn provide insights into microcephaly observed in diseases such as microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) and Roifman syndrome that are both caused by defective minor spliceosome.
小头畸形是一种毁灭性的发育缺陷,可由遗传突变引起,如 这会使微小的剪接体失活,或者最近的寨卡病毒感染。为了更好地理解 导致小头畸形的潜在分子和细胞缺陷,我们必须首先了解分子和细胞缺陷 细胞在正常发育过程中的变化。目前的提案扩大了我们的发现,即停用 在我们的U11条件基因敲除(CKO)小鼠中,与Emx1-Cre杂交的微小剪接体导致 出生时观察到的小头畸形。我们发现小头畸形的主要原因是丧失自我放大能力。 放射状胶质细胞(RGC)和延迟死亡的中间祖细胞(IPC)没有相应的 在早期皮质发育过程中神经元的丢失。尽管到E14完全失去了NPC,但正在开发的 突变的大脑皮层成功地产生了第四层神经元,这些神经元通常在E14出生/之后出生。我们发现这个 通过EDU PULSE/CHASE测量,神经元产生的变化与神经发生的增加有关 实验。基于这些复杂的表型,我们提出了三个目标来检验这一假设 小剪接体以细胞类型特有的方式起作用,告知细胞周期调节、NPC能力和 神经元的产生。目标1a中提出的实验旨在阐明精确的细胞周期调控。 RGC和IPC以及这两种类型的细胞是在经历自我放大还是神经源性细胞 组织。在目标1b中,我们探索了U11缺失的RGC和IPC的变化如何影响神经元的产生。在AIM 2、目的是了解U11缺失的细胞型特异性效应的分子基础。其中之一 RGC的独特之处在于,与IPC相比,它们分裂得更快,因此AIM中提出的实验 2检验细胞周期速度与U11基因缺失易感性的假设。另一种可能性是 在目标2b中提出的实验是,每种细胞类型都有一个含有微小内含子基因的独特标记。 (MiGs),这可能使细胞对U1丢失具有抵抗力/易感性。最后,RNAseq数据显示P53- U11缺失组织中定量的细胞凋亡途径和细胞周期缺陷。目标3a中提出的实验 检测挽救细胞周期缺陷是否能阻止P53介导的细胞凋亡,抑或是P53介导的凋亡 与细胞周期缺陷无关。Aim 3b测试了这样一种想法:如果P53被消融,它会挽救细胞周期还是 细胞死亡,进而拯救小头畸形症。总而言之,我们将发现这种新的基因调控形式在 皮质发育,进而提供对在以下疾病中观察到的小头畸形症的见解 小头骨质增生性原始性侏儒症1型(MOPD1)和Roifman综合征 由有缺陷的小剪接体引起。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Disrupted minor intron splicing is prevalent in Mendelian disorders.
  • DOI:
    10.1002/mgg3.1374
  • 发表时间:
    2020-09
  • 期刊:
  • 影响因子:
    2
  • 作者:
    Olthof AM;Rasmussen JS;Campeau PM;Kanadia RN
  • 通讯作者:
    Kanadia RN
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RAHUL N KANADIA其他文献

RAHUL N KANADIA的其他文献

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{{ truncateString('RAHUL N KANADIA', 18)}}的其他基金

Understanding the role of minor intron splicing in cortical development
了解小内含子剪接在皮质发育中的作用
  • 批准号:
    9888451
  • 财政年份:
    2018
  • 资助金额:
    $ 36.61万
  • 项目类别:
The Role of Alternative Splicing Factor Sfrs10 in Neural Development
选择性剪接因子 Sfrs10 在神经发育中的作用
  • 批准号:
    8223205
  • 财政年份:
    2011
  • 资助金额:
    $ 36.61万
  • 项目类别:
The Role of Alternative Splicing Factor Sfrs10 in Neural Development
选择性剪接因子 Sfrs10 在神经发育中的作用
  • 批准号:
    8188786
  • 财政年份:
    2011
  • 资助金额:
    $ 36.61万
  • 项目类别:
The Role of Alternative Splicing Factor Sfrs10 in Neural Development
选择性剪接因子 Sfrs10 在神经发育中的作用
  • 批准号:
    8420479
  • 财政年份:
    2011
  • 资助金额:
    $ 36.61万
  • 项目类别:
The Role of Alternative Splicing Factor Sfrs10 in Neural Development
选择性剪接因子 Sfrs10 在神经发育中的作用
  • 批准号:
    7788630
  • 财政年份:
    2010
  • 资助金额:
    $ 36.61万
  • 项目类别:

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