Wnt5 and the Patterning of the Olfactory map

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 DESCRIPTION (provided by applicant): Studying insect olfactory map development is important not only for gleaning the rules of neural map construction but also for finding ways to combat insect-borne diseases. Our long-term goal is to elucidate the mechanisms by which the insect olfactory map develops using the Drosophila antennal lobe (AL) as a model. Recent work showed that the targeting of dendrites of the second-order neurons, the projection neurons (PNs), is sufficient to pioneer the olfactory map. Notwithstanding these advances, how the final arrangement of PN dendrites is attained remains unknown. We present evidence that the PN dendrites undergo novel rotational movements to attain their final positions, a process that is regulated by the non-canonical Wnt5 ligand and its receptor, Derailed/Ryk (Drl). We show that Wnt5 repels the PN dendrites, while Drl represses Wnt5 signaling. Non-canonical Wnts play crucial roles in morphogenesis, but the mechanisms by which they direct cell movements are obscure. We now show that mutation in the Van Gogh (Vang) gene strongly mimics the wnt5 phenotype. Vang, a tetraspanin, is a member of the core planar cell polarity (PCP) proteins, which play fundamental roles in cell orientation during morphogenesis. Despite their extensive functions, the extracellular cues controlling PCP functions are mysterious. We propose that Vang acts downstream of Wnt5 to direct PN dendrites migration and that Drl represses Wnt5 signaling by binding to Vang. Our specific Aims are to: (1) Elucidate Vang's cellular and developmental functions in AL development. This will be achieved through cell-type specific disruption of Vang function in the PNs, and direct observation of PN dendritic migration in the Vang mutant. (2) Elucidate Vang's genetic and molecular functions in the Wnt5 signaling pathway. This will be accomplished through assessment of genetic interactions between Vang, drl and wnt5 in vivo, and of biochemical interaction between Vang and Drl in vitro. Accomplishment of the Specific Aims will shed light on an important stage in insect olfactory circuit assembly, when dramatic rotational rearrangement of the PN dendrites occurs. The work will also show that the novel rotation of PN dendrites employs a conserved mechanism, Vang, which also regulates the rotation of cells in other tissues. The work will thus yield insights into the mechanisms of dendritic guidance, which is poorly understood. Lastly the work will help resolve the long-standing controversy of whether Wnts play an instructive role in planar polarity signaling. Knowledge gain from this work will open new avenues of inquiries in the study of non-canonical Wnt signaling and dendrite guidance.