The nervous system is a vastly complex network which develops through intricate and tightly regulated processes. One critical aspect of neurodevelopment is the formation of connections between neurons. Synapses form through a series of complex steps to ensure their lasting functionality throughout the life of an organism. The regulation of these steps is essential for proper synaptic organization, but the molecular mechanisms that underlie these events remain incompletely understood. Knowledge of these processes is central to the understanding of cellular events that occur during synaptic development, as well as the mechanisms which may be impaired in neurodevelopmental disorders, including autism. The goal of this F31 Ruth L. Kirchstein NRSA is to address fundamental questions about synaptic development. This proposal aims to elucidate a novel mechanism of synaptic development by investigating the cell surface receptor LRP4. This protein has a well-defined role at the developing mammalian neuromuscular junction (NMJ), but has recently been found at other synapses, with more enigmatic functions. At the mammalian NMJ, LRP4 functions postsynaptically in conjunction with Agrin and MuSK. At other synapses, including in the Drosophila CNS, LRP4 has been found presynaptically and independent of Agrin and MuSK. Preliminary data at the Drosophila larval NMJ also indicates an important role in synaptic development. This synapse provides an opportunity for dissection of a novel mechanism by which LRP4 functions during synaptic development, given the availability of molecular genetics tools and achievability of single synapse resolution. The cellular events governed by LRP4 at the Drosophila NMJ will be assessed using high resolution imaging, genetics, and biochemistry. Expression studies will inform whether LRP4 functions at the presynapse or postsynapse to promote development. Analysis of loss of function phenotypes will determine the developmental processes regulated by these genes of interest. Genetic and biochemical approaches will eludicate the pathway by which these processes are regulated. Overall, these studies will provide unique insights into a novel role for LRP4 in regulating synaptic development. This project will inform the understanding of fundamental developmental mechanisms, and provide insights into neurodevelopmental disorders.
Within the nervous system, neurons must form connections to communicate with each other. These synaptic connections are essential to the function of the nervous system, but the complex processes by which they form are not completely understood. In this study, I will investigate a novel mechanism by which synaptic development occurs in order to better understand its role in disease and the overall development of the nervous system.
