Local protein synthesis enables distinct biological functions of subcellular compartments. Neuronal axons are far apart from the cell body. Although thousands of mRNAs are present in axons and dysfunctional axonal protein synthesis is linked to multiple disorders, our understanding of the molecular mechanisms underlying the local protein synthesis in axons is largely limited. Axon arborization plays a critical role in nervous system function because it defines a territory for proper synaptic connection. The long-term goal is to elucidate the mechanisms that govern localized protein synthesis and their role in axon arborization. The objective of current application is to gain mechanistic insights on the role and the regulation of the cytoplasmic polyadenylation element binding protein (CPEB) in axonal protein synthesis and axon arborization by using Drosophila as a model system. CPEB controls target protein translation through cytoplasmic de- and poly-adenylation. Our preliminary studies support a model that a Drosophila CPEB, Orb2 suppresses the protein synthesis of Down syndrome cell adhesion molecule (Dscam) in the cell body through cytoplasmic deadenylation and mediates Dscam mRNA transport to axon where Wallenda/Dual leucine zipper kinase (Wnd/DLK) de-represses the translational suppression by Orb2. The newly developed innovative approach will be used to study the following two aims.
In Aim 1, the role of Orb2 in axonal Dscam protein synthesis will be determined.
In Aim 2, the regulatory mechanism of Orb2 by Wnd will be studied. The physiological role of identified mechanisms will be determined using axon arborization in vivo. Orb2/CPEB is important for long-term memory formation. Dscam is implicated in multiple brain disorders. Wnd/DLK plays a key role in multiple neuronal events. Therefore, the contribution will be significant because it will provide a novel role of Orb2/CPEB in axonal protein synthesis, a novel axonal protein synthesis regulation by Wnd/DLK, and a mechanism of Dscam expression and localization in axons. The expected outcome is the novel molecular regulatory mechanisms in axonal protein synthesis and their role in axon arborization. Understanding the molecular mechanisms of axonal protein synthesis and arborization will ultimately help developing effective treatment to brain disorders.
Neuronal axons are essential for proper brain wiring and travel long distance from the cell body, which necessitates localized protein synthesis in axons. Although dysfunctional axonal protein synthesis is linked to multiple brain disorders, our understanding of the molecular mechanisms underlying the local protein synthesis in axons is largely limited. This proposal aims to elucidate how axonal protein synthesis is regulated at the molecular level, which will provide essential basic knowledge for developing effective treatment for the brain disorders that are caused by dysregulated axonal protein synthesis.