Role of KCNB1-Integrin Complexes in neurodevelopment

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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.