Role of the immunoglobulin superfamily member Basigin in sensory neuron dendrite morphogenesis in Drosophila

摘要

Neurons develop highly stereotypic dendritic arbors that influence establishment of proper connections and integration of information they receive to generate an appropriate output. Morphogenesis of dendrites is coordinated by both cell-intrinsic and extrinsic factors. Recent studies have begun to elucidate how interactions between neurons shape dendrite morphogenesis. However, influence of the substrate upon which neurons grow their dendritic arbors in this process is relatively poorly understood. Here I have used the peripheral sensory neurons of the Drosophila larva that grow dendrites over epithelial cell substrates to gain insights into how interactions with the substrate may influence dendrite development. In this thesis, I present data showing that Basigin, an immunoglobulin superfamily member, has somatodendritic and axonal localization in sensory neurons, and is enriched at cell borders and beneath class IV dendrites in epithelial cells. Loss of function analyses indicate that Basigin is required both in neurons and epithelial cell substrates for proper morphogenesis of the highly complex dendrites of class IV sensory neurons. Reduced innervation of the dendritic field of basigin mutant neurons was observed even at an immature stage, indicating a requirement of Basigin in these neurons for developmental elaboration of dendritic arbors. Structure-function analysis revealed that membrane-tethering of Basigin on the neuronal surface is essential for its function. In addition, a highly conserved tri-basic motif consisting of positively charged residues that may bind cytoskeletal adaptor proteins is required for its function in neurons. Results of genetic interaction analysis suggest that Basigin-mediated regulation of dendrite morphogenesis does not involve Integrin and matrix metalloproteinases, both of which have been implicated in Basigin function in other cellular contexts. I show that Basigin exhibits genetic interaction with Tropomodulin, an actin-capping protein, suggesting that they function in the same molecular pathway in regulating dendrite development. Taken together, data presented in this thesis support a model in which interaction between Basigin on the surfaces of neurons and epithelial cells regulate the underlying cytoskeleton within dendrites to influence their development. Thus, these results identify a novel molecular pathway that may mediate communication between neurons and their substrates that is essential for proper dendrite morphogenesis.