Collaborative Research: Molecular mechanisms of dendrite development, maintenance and plasticity: in vivo single-neuron analysis in C. elegans

合作研究：树突发育、维持和可塑性的分子机制：线虫体内单神经元分析

• 批准号: 1755019
• 负责人: Michael Francis
• 金额: $ 61.65万
• 依托单位: University of Massachusetts Medical School
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755019&HistoricalAwards=false
• 关键词: Collaborative; Research; Molecular; mechanisms; dendrite

Brain development involves the formation and fine-tuning of complex networks of connections between nerve cells. These connections occur at specialized sites of nerve cell contact, often formed on thorn-like structures (called spines) that protrude from the nerve cells. Precisely-controlled structural changes in spines are important for proper learning and memory. Some neuro-developmental disorders are the result of improper spine outgrowth, or a failure to properly maintain spines. These dysfunctions result in abnormalities in nerve cell communication that decrease learning and memory performance. Preliminary work for the present project has shown that connections between some nerve cells in the nematode worm Caenorhabditis elegans have spine-like structures, similar to those in the human brain. This project will investigate the mechanisms by which spines are formed during normal development, and maintained throughout life. The research uses C. elegans worms because of the powerful genetic tools developed in this species for identifying and understanding molecular pathways that control basic cell functions. By applying these tools to the mechanisms underlying spine outgrowth and maintenance, we expect to gain critical novel insights into the requirements for healthy brain function. Important insights into neurodevelopmental disorders may also be provided. This research project will also support the training of future scientists by providing mentored research experiences for undergraduate and graduate students, as well as local high school teachers. Recruitment for these activities will emphasize participants from under-represented groups in science.Most excitatory synapses in the mammalian brain occur at dendritic spines, which are small actin-rich membrane protrusions that house neurotransmitter receptors and other signaling machinery. Spines are essential structures in synaptic connectivity and plasticity, and underlie important processes of learning and memory. Despite recent progress in defining molecular mechanisms that regulate spine morphological changes, many questions about the basic biology of spine formation, maintenance and plasticity remain unanswered. The role of the extracellular matrix (ECM) in regulating spine development and maintenance is particularly poorly understood. The present studies will employ genetic tools available in the nematode worm Caenorhabditis elegans to identify and characterize molecular pathways involved in synapse development and plasticity. Preliminary work revealed that excitatory synaptic contacts onto C. elegans GABAergic neurons occur at spine-like protrusions. This collaborative project, incorporating expertise from the Lemons, Francis and B'nard labs, will investigate ECM-mediated mechanisms for guiding dendrite development and dynamics, as well as applying unbiased forward genetic screening to uncover novel cellular and molecular pathways that regulate dendritic spines in vivo.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

大脑发育涉及神经细胞之间复杂连接网络的形成和微调。这些连接发生在神经细胞接触的特定部位，通常形成在从神经细胞突出的刺状结构（称为棘）上。精确控制的脊椎结构变化对正确的学习和记忆很重要。一些神经发育障碍是由于脊柱生长不当，或未能正确维护脊柱。这些功能障碍导致神经细胞通讯异常，从而降低学习和记忆能力。本项目的初步工作表明，线虫秀丽隐杆线虫中的一些神经细胞之间的连接具有类似于人类大脑的棘状结构。本项目将研究脊椎在正常发育过程中形成并在整个生命过程中保持的机制。本研究采用C.蠕虫是因为在这个物种中开发了强大的遗传工具，用于识别和理解控制基本细胞功能的分子途径。通过将这些工具应用于脊柱生长和维护的机制，我们期望获得对健康大脑功能要求的关键新见解。也可以提供对神经发育障碍的重要见解。该研究项目还将通过为本科生和研究生以及当地高中教师提供指导性研究经验来支持未来科学家的培训。哺乳动物大脑中的大多数兴奋性突触发生在树突棘上，树突棘是一种富含肌动蛋白的小膜突起，容纳神经递质受体和其他信号机制。棘是突触连接和可塑性的基本结构，并且是学习和记忆的重要过程的基础。尽管最近在定义调节脊柱形态变化的分子机制方面取得了进展，但有关脊柱形成，维持和可塑性的基础生物学的许多问题仍然没有答案。细胞外基质（ECM）在调节脊柱发育和维持中的作用尤其知之甚少。目前的研究将采用遗传工具，在线虫秀丽隐杆线虫识别和表征参与突触发育和可塑性的分子途径。初步工作表明，兴奋性突触接触到C。线虫GABA能神经元出现在棘状突起处。这个合作项目，结合了Lemons，弗朗西斯和B'nard实验室的专业知识，将研究ECM介导的指导树突发育和动力学的机制，该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值进行评估来支持和更广泛的影响审查标准。

项目成果

Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity

整合素在运动神经元连接的发展中具有细胞类型特异性的作用

• DOI: 10.3390/jdb7030017
• 发表时间: 2019
• 期刊: Journal of Developmental Biology
• 影响因子: 2.7
• 作者: Oliver, Devyn;Norman, Emily;Bates, Heather;Avard, Rachel;Rettler, Monika;Bénard, Claire Y.;Francis, Michael M.;Lemons, Michele L.
• 通讯作者: Lemons, Michele L.