Grant: Operating Grant

Dendrites are specialized tree-like structures that allow neurons to receive sensory and synaptic input within the nervous system. Diseases associated with mental retardation, including Down Syndrome, Rett Syndrome and Fragile-X Syndrome among others, are often associated with the disruption of the normal architecture of neuronal dendrites. This may result from altered dendrite development, and the goal of our research is to uncover novel cellular and molecular mechanisms that underlie the tree-like patterns of growth, branching and targeting of dendrites. Dendrites in the fruit fly model system Drosophila are remarkably similar to dendrites in humans, displaying many of the same molecular and functional properties. We recently used this model to discover that two proteins, called Lola and Spire, are essential for specific aspects of the growth and branching of dendritic trees. We hypothesize that Lola acts in the nucleus of neurons to regulate the abundance of Spire, which then controls the underlying molecular "skeleton" of dendrites and the delivery of other essential building materials. The objectives of this research grant are to 1) investigate how Spire regulates the cytoskeleton of dendritic trees and the distribution of building materials to them, and 2) discover factors that cooperate with Spire in developing dendrites and 3) determine whether Spire-like proteins in mice regulate dendrite development in a similar fashion in Purkinje neurons of the cerebellum. Based on previous experience, it is expected that these genetic studies in Drosophila will help to understand dendrite patterning in the human nervous system, and could lead to insight into the underlying causes of diseases that disrupt dendrite structure.