Molecular mechanisms of differentiation of habenular and thalamic neurons

缰核和丘脑神经元分化的分子机制

基本信息

  • 批准号:
    8373016
  • 负责人:
  • 金额:
    $ 38.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-01 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The habenula and thalamus arise from two closely related progenitor domains during embryogenesis and they play crucial roles in modulating the forebrain circuitry in a mature brain. The developmental mechanisms underlying the distinct thalamic and habenular connectivity, and the topographic projection of thalamic axons to specific cortical areas are still poorly understood at both transcriptional and axon guidance levels. Our long-term goal is to determine the molecular mechanisms that regulate thalamic and habenular identity and connectivity, and ultimately understand the brain disorders resulting from abnormal formation and/or function of the thalamus and habenula. The overall objective of this application is to determine the molecular control of the guidance decisions during the initial outgrowth of thalamic axons and their subsequent navigation to the cortex. Our central hypothesis is that Gbx2 controls the intrinsic responsiveness of thalamic axons to guidance cues encountered in their path to the cortex by regulating the modification of heparan sulfate and the expression of guidance receptors Robo1 and Robo2. Therefore, our proposed study will provide new insight into the important but less understood role of heparan sulfate in regulating axonal guidance. Furthermore, the elucidation of how Gbx2 controls the intrinsic responsiveness of thalamic axons will enhance our understanding on the establishment of the thalamic connectivity, including the topography of thalamocortical axons. The hypothesis has been formulated on the basis of results from our preliminary studies, including identifications of several downstream targets that may mediate Gbx2 function. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the role of modifications of heparan sulfate in the developing thalamus; and 2) Determine the molecular mechanism that regulates the topography of thalamocortical projections. We will combine in vitro studies (brain slice and explant culture, molecular biology, and biochemistry) and mouse genetics (chimeric, genetic mosaic, inducible genetic fate mapping and conditional knock-out). The approach is innovative, because it employs state-of-the-art mouse genetics, and utilizes different fluorescence proteins to identify all thalamic axons and those with Gbx2 deletion to study the topography of thalamocortical projections. The proposed studies are expected to significantly enhance our understanding on the transcriptional regulation and axonal guidance signaling in the establishment of thalamic projections to the cortex. Ultimately, such knowledge will contribute to our understanding on the pathogenesis or susceptibility of neurological illnesses, such as epilepsy, schizophrenia, bipolar disorder, and autism. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because abnormal formation and function of the habenula and thalamus have been linked to neurological illnesses, such as epilepsy, schizophrenia, bipolar disorder, sleep disorders, and autism. Elucidation of the molecular mechanisms that govern the generation of thalamic and habenular connectivity will be ultimately expected to augment our understanding of the pathogenesis or conditions predisposing to the aforementioned brain disorders.
描述(由申请人提供):缰核和丘脑在胚胎发生期间由两个密切相关的祖细胞结构域产生,它们在调节成熟大脑中的前脑回路中起关键作用。不同的丘脑和缰连接,以及丘脑轴突的拓扑投影到特定的皮质区域的发展机制仍然知之甚少,在转录和轴突指导水平。我们的长期目标是确定调节丘脑和缰的身份和连接的分子机制,并最终了解丘脑和缰的异常形成和/或功能导致的大脑疾病。本申请的总体目标是确定在丘脑轴突的初始生长及其随后的导航到皮质期间的指导决策的分子控制。我们的中心假设是,Gbx 2控制丘脑轴突的内在反应,以指导线索,在其路径中遇到的皮质通过调节硫酸乙酰肝素的修改和指导受体Robo 1和Robo 2的表达。因此,我们的研究将为硫酸乙酰肝素在调节轴突导向中的重要但鲜为人知的作用提供新的见解。此外,Gbx 2如何控制丘脑轴突的内在反应性的阐明将增强我们对丘脑连接的建立,包括丘脑皮质轴突的拓扑结构的理解。该假设是根据我们初步研究的结果制定的,包括鉴定可能介导Gbx 2功能的几个下游靶点。在强有力的初步数据的指导下,这一假设将通过追求两个特定的目标进行检验:1)确定硫酸乙酰肝素修饰在发育中的丘脑中的作用; 2)确定调节丘脑皮质投射地形的分子机制。我们将结合联合收割机体外研究(脑切片和外植体培养,分子生物学和生物化学)和小鼠遗传学(嵌合,遗传镶嵌,诱导遗传命运作图和条件敲除)。该方法是创新的,因为它采用了最先进的小鼠遗传学,并利用不同的荧光蛋白来识别所有丘脑轴突和Gbx 2缺失的轴突,以研究丘脑皮质投射的地形。这些研究将有助于我们更好地理解丘脑向皮层投射的转录调控和轴突导向信号。最终,这些知识将有助于我们了解神经系统疾病的发病机制或易感性,如癫痫,精神分裂症,双相情感障碍和自闭症。 公共卫生相关性:这项拟议中的研究与公共卫生有关,因为缰核和丘脑的异常形成和功能与神经系统疾病有关,如癫痫、精神分裂症、双相情感障碍、睡眠障碍和自闭症。阐明控制丘脑和缰连接产生的分子机制,最终有望增加我们对上述脑疾病发病机制或易感条件的理解。

项目成果

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JAMES Y.H LI其他文献

JAMES Y.H LI的其他文献

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{{ truncateString('JAMES Y.H LI', 18)}}的其他基金

Combinatorial function of Foxp1/2/4 in Purkinje cell diversification and cerebellar development
Foxp1/2/4在浦肯野细胞多样化和小脑发育中的组合功能
  • 批准号:
    10338197
  • 财政年份:
    2021
  • 资助金额:
    $ 38.23万
  • 项目类别:
Combinatorial function of Foxp1/2/4 in Purkinje cell diversification and cerebellar development
Foxp1/2/4在浦肯野细胞多样化和小脑发育中的组合功能
  • 批准号:
    10604350
  • 财政年份:
    2021
  • 资助金额:
    $ 38.23万
  • 项目类别:
MOLECULAR REGULATION OF LINEAGE SPECIFICATION OF THE MOUSE CEREBELLUM
小鼠小脑谱系规范的分子调控
  • 批准号:
    9923763
  • 财政年份:
    2018
  • 资助金额:
    $ 38.23万
  • 项目类别:
MOLECULAR REGULATION OF LINEAGE SPECIFICATION OF THE MOUSE CEREBELLUM
小鼠小脑谱系规范的分子调控
  • 批准号:
    10158523
  • 财政年份:
    2018
  • 资助金额:
    $ 38.23万
  • 项目类别:
Molecular Regulation of Lineage Specification of the Mouse Cerebellum
小鼠小脑谱系规范的分子调控
  • 批准号:
    10400178
  • 财政年份:
    2018
  • 资助金额:
    $ 38.23万
  • 项目类别:
Molecular mechanisms of differentiation of habenular and thalamic neurons
缰核和丘脑神经元分化的分子机制
  • 批准号:
    8502557
  • 财政年份:
    2012
  • 资助金额:
    $ 38.23万
  • 项目类别:
Molecular mechanisms of differentiation of habenular and thalamic neurons
缰核和丘脑神经元分化的分子机制
  • 批准号:
    8869035
  • 财政年份:
    2012
  • 资助金额:
    $ 38.23万
  • 项目类别:
Molecular mechanisms of differentiation of habenular and thalamic neurons
缰核和丘脑神经元分化的分子机制
  • 批准号:
    8688055
  • 财政年份:
    2012
  • 资助金额:
    $ 38.23万
  • 项目类别:
The Role of Alternative Splicing of Fgf8 in Mouse Development
Fgf8 选择性剪接在小鼠发育中的作用
  • 批准号:
    7354066
  • 财政年份:
    2007
  • 资助金额:
    $ 38.23万
  • 项目类别:
The Role of Alternative Splicing of Fgf8 in Mouse Development
Fgf8 选择性剪接在小鼠发育中的作用
  • 批准号:
    7758357
  • 财政年份:
    2007
  • 资助金额:
    $ 38.23万
  • 项目类别:

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