Role of KCNB1-Integrin Complexes in neurodevelopment

一个长期困扰神经生物学家的问题是，大脑是如何形成高度组织化的结构的。脑细胞（神经元）并不是随机分布在大脑中；每个发育中的细胞都有自己的旅程，在大脑中占据一个精确的位置。当大脑在早期胚胎中开始成形时，神经元在一个特定的区域产生，它们从这个区域迁移出来，有时会移动很远的距离到达它们的最终位置。新形成的神经元延伸出被称为轴突和树突的薄突起，与其他神经元形成连接，形成高度组织的相互连接的细胞网络。众所周知，神经元在行进过程中受到远程和短程化学线索的引导，但迁移的神经元也通过交换电信号相互“交谈”。后一种信号还指导神经元的迁移选择，并影响它们最终与哪些其他神经元连接。先前的研究表明，神经元使用“传感器”（电反应蛋白的复合物）将电信号转化为运动和网络反应，但这是如何发生的目前尚不清楚。这个项目将阐明这些传感器的工作方式，以及它们用来影响哺乳动物大脑中神经回路形成的机制。除了这些科学目标之外，该项目还将为本科生和高中生提供完善的培训计划，使他们接触到重要的研究领域，为他们提供实验技术的实践经验，并为他们未来在科学领域的成功追求做出贡献。这个项目的结果有望揭示以前未被研究的脑回路发育的一个主要方面，这对先天性脑畸形和发育性脑障碍的介导具有重要意义。该项目揭示了一种新的皮层发育机制，即由电压门控钾通道（KCNB1）和α - 5- β - 5整合素（被称为整合素-KCNB1复合物）形成的大分子复合物，将新兴神经元结构的自发电活动转化为调节电路组装的生化信号。它结合了生物化学、免疫组织化学、共聚焦显微镜和动物研究（含有缺陷IKCs的KI小鼠）来建立受IKCs影响的发育过程及其产生的回路和相关行为之间的机制联系。了解由K+通道和整合素组成的大分子复合物如何塑造关键的神经发育过程，将为神经元回路及其相关脑结构发育的分子机制提供一个新的窗口。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

One of the enduring questions that puzzles neurobiologists is how the brain achieves its highly organized structure. Brain cells (neurons) do not randomly populate the brain; each developing cell undertakes its own journey to occupy a precise position in the brain. When the brain begins to take shape in the early embryo, neurons are generated in a specific zone that they migrate out from, sometimes moving great distances to reach their final position. The newly formed neurons extend thin projections, called axons and dendrites, to form connections with other neurons, giving rise to highly organized networks of interconnected cells. It is well known that neurons are guided by both long-range and short-range chemical clues during their journey, but the migrating neurons also "talk" to each other by exchanging electrical signals. The latter signals also guide neurons' migration choices, and influence which other neurons they ultimately connect with. Previous research shows that neurons use "sensors" (complexes of electrically responsive proteins) to transduce electrical signals into movement and networking responses, but how this happens is currently unknown. This project will elucidate the ways in which these sensors work, and the mechanisms they use to affect the formation of neural circuits in the mammalian brain. In addition to these scientific goals, this project will support a well-established training program for undergraduate and high-school students that exposes them to prominent areas of research, gives them hands-on experience with experimental techniques, and contributes to their successful pursuit of future careers in science. The results of this project are expected to shed new light on a previously unstudied, major aspect of brain circuit development that has important implications for mediating congenital brain malformations and developmental brain disorders. This project deciphers a novel mechanism of cortical development whereby macromolecular complexes formed by voltage-gated potassium channels (KCNB1) and alpha5-beta5 integrins, dubbed IKCs (Integrin-KCNB1-Complexes), transduce the spontaneous electrical activity of emergent neuronal structures into biochemical signals that regulate circuit assembly. It uses a combination of biochemistry, immunohistochemistry, confocal microscopy and animal studies (KI mice harboring defective IKCs) to establish mechanistic links between the developmental processes influenced by IKCs and their resultant circuits and associated behaviors. Understanding how macromolecular complexes consisting of K+ channels and integrins can shape critical neurodevelopmental processes will provide a new window into the molecular mechanisms that underlie the development of neuronal circuits and their associated brain architectures.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.