Neurotrophin, Toll and Trk-like functional relationships in the Drosophila central nervous system. (360G-Wellcome-094175_Z_10_Z)

Building on our discovery of Drosophila neurotrophins (DNTs), we aim here to identify the DNT receptor repertoire. Our preliminary data have revealed that DNT1 and DNT2 most probably bind Toll6 and Toll7 receptors, and might also bind p75-like and divergent Trk-like receptors whose evolution may have involved the separation of receptor modules. Drosophila Toll and mammalian Toll-like receptors (TLRs) are involved in innate immunity, while mammalian NTs link nervous system structure and function from development to cognition. There are potential functional overlaps between NTs and TLRs, since mammalian NTs are also involved in immunity, and TLRs have functions in the central nervous system (CNS). It is compelling to find out to what extent the NT and Toll protein families functionally interact, and what the full receptor repertoire is available to NTs in fruit-flies. This is essential in order to continue using Drosophila to understand the brain and to model human brain diseases. The key goals are: Objective 1 To investigate with genetic in vivo analyses the functions of Toll6 and Toll7 in the Drosophila CNS. Objective 2 To test biochemically if Toll6 and Toll7 function as DNT receptors. Objective 3 To test p75-like and Trk-like receptors as candidate DNT receptors.