Using Drosophila to investigate the roles of conserved IgSF proteins in neuronal differentiation and axon guidance.

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The ability of the brain to function properly relies upon patterned development of neurons and the controlled establishment of synaptic connections. The overall objective of our research program is to use the Drosophila model system to understand these processes at a molecular and cellular level. We are investigating how extrinsic signals influence the differentiation of neurons and the guidance of axons via three transmembrane proteins of the immunoglobulin superfamily (IgSF) known as Ihog, Boi and Tutl. In the previous 3-yr term of this Discovery Grant, students in the van Meyel lab have made exciting discoveries that implicate Ihog, Boi and Tutl as key regulators of neuronal differentiation and/or axon guidance. These IgSF proteins are conserved in other species including mammals, and they are comprised of ectodomains with Ig-like and fibronectin type III repeats, a transmembrane domain, and a cytoplasmic tail. We have found recently that Ihog and Boi are functionally redundant and essential for signaling via the Hedgehog (Hh) pathway. Hh is an important determinant of neuronal differentiation in the retina, spinal cord, brain, and many other cell types. We have also found that Tutl is important patterned growth and guidance of axons and dendrites, but the mechanism of action of Tutl remains completely mysterious. The specific objectives of this research program are to: 1) determine how Ihog and Boi participate in the Hedgehog signaling pathway, 2) characterize new functions for Ihog and Boi in axon guidance and Hh transport and 3) investigate the role of Tutl in axon guidance. This Discovery Grant builds on the foundation of research funded over the previous 3-yr period to identify novel axon guidance molecules. Our innovative research program provides excellent conceptual and technical training for students, where our long-term goal is to explain at a molecular level the principles upon which neural circuits in the brain are built and assembled during development.