Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization

The sensory and motor functions of the nervous system depend on the establishment of precise connections between different types of neurons and target cells during development. In the developing nervous systems of both vertebrates and invertebrates, neurons express a wide diversity of cell adhesion molecules, which mediate interactions that are essential for specifying target selection and connectivity patterns. This proposal will study the molecular control of circuit development through a combination of genetic and biophysical approaches in which binding affinities and cell surface localization of cell adhesion molecules are manipulated and their effects on neural circuit formation are studied in the larva fruit fly. The proposed research will have a significant impact on multiple research fields due to the generality of the phenomena to be studied. Moreover, integrating computational and structural biology with developmental neuroscience is likely to stimulate similar collaborative efforts in these fields. In terms of training, students and postdocs working on this project will develop a deep appreciation of both computational and experimental work, thus providing exemplars for broadly trained interdisciplinary scientists. Women scientists constitute over 50% of the participating groups. The research program includes training of high school and undergraduate students, many of whom are from underrepresented minorities in sciences, through summer internships. The team will continue partnering with a network of high schools across lower-income districts and minority serving colleges, and run the DREAM-High cloud computing course for high school students that increases student awareness of and interest in biological sciences, empowers students to adopt scientific reasoning and critical-thinking skills, and inspires students to seek post-secondary education in related fields.This project will investigate the effects of binding affinity and cell surface availability of cell adhesion molecules (CAMs) on circuit formation in Drosophila. The study will focus on the larval neuromuscular system and mushroom body development. At the molecular level, the focus will be on two interacting groups of CAMs, the Dprs (Defective in Proboscis extension Response) and the DIPs (Dpr Interacting Proteins). The choice of these proteins and anatomical structures is based on the deep understanding of the biophysical properties of DIPs and Dprs that has emerged over the past few years, and on the demonstration of their crucial roles in the development of these anatomical structures. Here, by examining various Dpr/DIP cognate pairs in different neurodevelopmental settings, the findings should deepen currently limited knowledge of the in vivo consequences of altering avidity using both changes in binding affinities and in expression levels. A particular focus will be on the phenomenon of cis inhibition, whereby interactions between cognate binding partners on the same cell compete with trans binding to partners on apposed cells. The underlying hypothesis is that cis-inhibition is a key regulatory mechanism in neural development.This project is jointly funded by the Neural Systems Cluster in IOS and the Molecular Biophysics Cluster in MCB of the Directorate for Biological Sciences.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.