The Frizzled Nuclear Import Pathway in Synapse Development

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DESCRIPTION (provided by applicant): The goal of this project is to elucidate the genetic programs that are regulated during synaptic development and activity-dependent plasticity. Recent advances in the study of nuclear functions reveal an unprecedented dynamics in the organization of nuclear subdomains which coordinate gene expression. However, the physiological pathways that regulate these dynamics are largely unknown. We have identified a critical transduction cascade, involving a member of the Wnt family and its receptor, in the communication between the synapse and the nucleus during activity-dependent synaptic growth. Essential roles of Wnts in synapse development and plasticity have also been uncovered in the mammalian brain, and a number of cognitive disorders, such as schizophrenia, bipolar disorder, and Alzheimer's disease show alterations in Wnt signaling. Thus, understanding how Wnts function in the brain is a highly significant area with important clinical implications. Our studies demonstrate that Wnt signaling at synapses activates a novel signaling pathway, the Frizzled Nuclear Import (FNI) pathway, in which a fragment of the Wg receptor, DFrizzled2 (DFz2), is imported into the nucleus. Within the nucleus, this DFz2 fragment, together with the A-type lamin, Lamin-C, establishes a specialized subdomain, which regulates gene expression by controlling mRNA biogenesis. Importantly, alterations in A-type lamins have been involved in a group of hereditary disorders, the laminopathies, which have devastating impact on the function of the neuromuscular system. In this project we propose to investigate the function of this nuclear subdomain in activity-dependent synaptic plasticity. In particular, we propose to (1) determine the role of the nuclear subdomain in controlling nuclear mRNA polyadenylation and to identify the genes that are regulated by this pathway, (2) determine the dynamics of the nuclear subdomain during motorneuron stimulation, and (3) begin the characterization of an important gene regulated by this transduction cascade. We predict that these studies will be highly significant for our understanding of how synaptic events are communicated to the nucleus to regulate gene expression. Ultimately, we expect that the proposed studies will be highly relevant to our understanding of cognitive disorders associated with the malfunction of Wnt signaling and to identify the cellular events that are altered in laminopathies. PUBLIC HEALTH RELEVANCE: A fundamental property of synaptic connections in the nervous system is their ability to change in response to experiences, a process that is referred to as synaptic plasticity. Studies in many systems show that a mechanism underlying this event relies on the regulation of genes within the nucleus. Thus, significant research efforts have been dedicated to understanding how synaptic connections communicate with the nucleus. In our research, we have uncovered a novel signaling pathway that, at least in part, mediates this communication. This pathway involves a member of a protein family, the Wnts and its receptor, which appears fundamental for the development of synaptic connections. These finding are particularly important, given that in humans alterations in Wnt signaling are associated with cognitive disorders, such as schizophrenia, bipolar disorder, and Alzheimer's disease. Thus, understanding this pathway may provide important insight into the causes of these conditions. We have also found that the Wnt signaling pathway collaborates with a nuclear protein, an A-type lamin, in the regulation of gene expression. Interestingly, alterations in A-type lamins lead to devastating diseases of the neuromuscular system. In this project we will identify the genes that are regulated by Wnts and A-type lamins, examine the properties of a nuclear region where this regulation is accomplished, and begin to characterize the function of the regulated genes in synapse development and plasticity. These studies, which will be conducted in a powerful model system amenable to sophisticated genetic techniques, the fruit fly Drosophila, is expected to provide significant advances to our understanding of the processes by which experiences modify the synaptic connections in the brain. In addition, by elucidating the mechanisms underlying these events, we hope to contribute to the development of clinical strategies to ameliorate or cure laminopathies and cognitive disorders associated with malfunction of Wnt signaling.