Investigation of PHR Signaling in C. elegans

Abstract

The nervous system consists of billions of neurons interconnected through specialized connections known as synapses. When and where these synapses form determines the functionality of the nervous system, and abnormal synaptic development has been linked to a variety of disorders such as autism and epilepsy. In addition, understanding how synapses are formed could lead to treatments for a variety of conditions characterized by a loss of synaptic connectivity, including Alzheimer's disease and stroke. Therefore, understanding the molecular processes that regulate the formation of synapses has become a major goal of modern neuroscience research. To form a synapse, a neuron must grow an axon, guide that axon to its proper target, and then form a synaptic connection. All of these processes must be coordinated to ensure synapses form at the correct time and in the correct location. One family of proteins that has become viewed as candidates to mediate this coordination is the Pam/Highwire/Rpm-1 (PHR) protein family. Over the past decade, the PHR proteins have emerged as key regulators of axon outgrowth and guidance, synapse formation, and degeneration. Given their central role in neurodevelopment, the discovery of any additional components of PHR signaling has the potential to increase our understanding of how a synapse is made, as well as identify therapeutic targets for pharmaceutical intervention. In the following dissertation, I outline two studies focused on the C. elegans PHR protein RPM-1 and the identification of novel mediators of RPM-1 signaling. In the first study, I provide evidence that the PP2C phosphatase PPM-1 functions as a second regulatory mechanism to RPM-1 to negatively regulate a MAP kinase cascade. This study provides insight into the regulation of MAP kinase signaling in neurons, as well as a new role for PP2C phosphatases in neural development. In the second study, I identify the nuclear anchorage protein ANC-1 as a novel binding partner of RPM-1. My genetic data also indicates that ANC-1 functions through the beta-catenin BAR-1 to regulate neurodevelopment. Our study highlights a new mechanism by which RPM-1 functions, as well as the first genetic link between RPM-1 and a pathway that is regulated by extracellular signals.