Molecular Mechanisms in Adhesion Protein Mediated Neuron-Neuron Recognition

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How neurons interact with one another to create the complex wiring diagram of a mature vertebrate brain is a major mystery. One of the many problems that arises is how neurons are "barcoded"; that is, how they distinguish self from non-self. This ability is essential since, without it, there would be nothing to prevent neurons from forming connections (synapses) with themselves, essentially creating a short circuit within the brain. The fundamental goal of this project is to understand how neurons are barcoded. Neuron-neuron recognition is mediated by protein-protein interactions. This project focuses on members of the Clustered Protocadherins (Pcdh) protein family that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". The research will involve computer simulations, biophysical measurements, and high-resolution microscopy experiments to experimentally validate and describe the barcoding mechanism in cells. A particularly important element of the research is the development of scientists with expertise in both computational and experimental work. The training of women and minority scientists is an integral component of the proposed research program. Both undergraduate and graduate minority students trained to be on a trajectory to become highly successful research scientists. The main objective of the project is to advance understanding of the molecular basis of neuron-neuron recognition. Cell-cell interactions are mediated by protein-protein interactions and the long-range goal of the research is to understand the underlying mechanisms. Specifically, how do protein-protein interactions involving cell surface proteins mediate highly specific cell-cell interactions. Given the complexity of the nervous system, neuron-neuron interactions offer a unique challenge in this regard. The research focuses on the clustered Protocadherins (Pcdhs) that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". These are neuronal barcoding proteins. The research involves computational studies to determine how homophilic specificity is coded on Pcdh-Pcdh interfaces, the design of mutants to test the hypotheses that are generated, and their testing experimentally. A second focus of the research is to elucidate the molecular basis of neuronal barcoding. A novel chain termination mechanism based on the assembly of crystalline-like "molecular zippers" in cell-cell interfaces has been proposed and is consistent with all available experimental data. The model will now be explored with multi-scale simulations, and in vitro and in vivo experimental studies. Notably, the model introduces new concepts in the molecular basis of cell-cell recognition. This project is supported by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.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.