The Frizzled Nuclear Import Pathway in Synapse Development

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

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.