Elucidating the mechanisms of gradient dependent and independent Wnt signaling in neuronal development

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Background The Wnt family of morphogens play crucial roles in animal development. Wnt proteins are known to generate gradient distributions within a tissue. However, it is not well understood how cells sense and interpret the Wnt gradients and to what extent the gradient distribution of Wnt contributes to animal development. Several studies, including our recent work, suggest that the gradient distribution of Wnts is dispensable in some aspects of animal development. This project is designed to increase our understanding of the gradient dependent and independent mechanisms of Wnt signaling using roundworm, Caenorhabditis elegans, as a model system. Progress Recently, we reported that Wnt instructs retraction of the neuronal processes or neurites, called neurite pruning. Time-lapse imaging of the developing PDB (posterior dorsal B) neuron in C. elegans revealed that some neurites undergo stereotyped pruning. We found the PDB neurite pruning depends on the Wnt signal. Strikingly, we did not observe pruning defects in the `non-diffusible Wnt' mutants. This observation suggests the gradient distribution of Wnt is not necessary for PDB neurite pruning. Interestingly, we found the position of PDB synapses depends on the Wnt gradient. Taken together, our results showed that a single neuron uses gradient dependent and independent Wnt signaling in a context-dependent manner. Research Objectives and Methods The long-term objective of this program is to understand the diverse actions of Wnt signaling in animal development. Our short-term objective is to expand our knowledge in gradient dependent and independent Wnt signaling in neuronal development using C. elegans. We will address the following specific research objectives.  1. Uncovering the mechanism of gradient independent Wnt signaling in neurite pruning. Using genetic screenings, we will uncover the downstream effectors of Wnt signaling in neurite pruning.  2. Uncovering the mechanisms of gradient dependent Wnt signaling in synapse positioning. Using genetic screenings, we will uncover Wnt effector genes that specifically function in controlling synapse positioning.  3. Understanding which neurodevelopmental events are Wnt gradient dependent. We will examine the various neurodevelopmental events known to be regulated by Wnt signaling using `non-diffusible wnt' mutants we generate. Impact We will reveal the mechanisms of Wnt-dependent neurite pruning and synapse positioning, both of which are still poorly understood. We will also characterize which neurodevelopmental processes depend on the Wnt gradient. Knowledge gained from our research will help better understand the complex actions of Wnt signaling in animal development. It will also help other researchers to test if the same mechanisms are present in other model organisms. We will raise internationally competitive next-generation scientists with broad expertise in genetics, molecular biology, and microscopy through our research program.