Vol.:(0123456789) 1 3 NeuroMolecular Medicine https://doi.org/10.1007/s12017-018-8515-9 REVIEW PAPER The Toll Pathway in the Central Nervous System of Flies and Mammals Anat Shmueli 1  · Tali Shalit 2  · Eitan Okun 1,3,4,5  · Galit Shohat‑Ophir 1,3 Received: 17 August 2018 / Accepted: 26 September 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Toll receptors, frst identifed to regulate embryogenesis and immune responses in the adult fy and subsequently defned as the principal sensors of infection in mammals, are increasingly appreciated for their impact on the homeostasis of the central as well as the peripheral nervous systems. Whereas in the context of immunity, the fy Toll and the mammalian TLR pathways have been researched in parallel, the expression pattern and functionality have largely been researched disparately. Herein, we provide data on the expression pattern of the Toll homologues, signaling components, and downstream efectors in ten diferent cell populations of the adult fy central nervous system (CNS). We have compared the expression of the dif- ferent Toll pathways in the fy to the expression of TLRs in the mouse brain and discussed the implications with respect to commonalities, diferences, and future perspectives. Keywords Toll · Drosophila · CNS · Innate immunity · TLR The Drosophila Toll Pathway The anti-microbial host defense of Drosophila involves fat body-mediated synthesis of peptides that are released into the open circulatory system where they attack invad- ing microorganisms (Zaslof 2002). Two distinct signaling pathways in the fat body cells of the fy are responsible for the transcription of the genes encoding these peptides. Acti- vated during Gram-positive bacterial and fungal infections, the Toll pathway controls the expression of the antifungal peptide Drosomycin, through the nuclear factor kappa- light-chain-enhancer of activated B cells (NF-kB) family member Dorsal-related immunity factor (Dif) (De Gregorio et al. 2001; Irving et al. 2001). The immune defciency (Imd) pathway is triggered mainly during Gram-negative infection and induces, through the NF-kB protein Relish, the produc- tion of many peptides directed against these bacteria (Bren- nan and Anderson 2004; Hofmann 2003). The Toll pathway, which was initially discovered and described in Drosophila melanogaster as critical for dorso- ventral patterning during embryogenesis, is also intimately involved in immune responses. These observations were subsequently recapitulated in mammals in which the Toll- like receptor (TLRs) pathway was shown to be central to organismal defense against invading pathogens. In Drosophila, Toll signaling is triggered by an acti- vated form of the Spätzle (Spz) protein prior to Toll activation. Cleaved Spz in turn interacts with Toll at the plasma membrane (Hashimoto et al. 1991; Towb et al. 2001) (Fig. 1a), resulting in a conformation change that generates an active Toll dimer (Fig. 1b). The cytoplas- mic domain of the newly formed dimer Toll interacts with the conserved Myeloid diferentiation primary response 88 (MyD88) adaptor protein. MyD88 then recruits Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12017-018-8515-9) contains supplementary material, which is available to authorized users. * Eitan Okun eitan.okun@biu.ac.il * Galit Shohat-Ophir galit.ophir@biu.ac.il 1 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel 2 The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel 3 The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel 4 The Paul Feder Laboratory on Alzheimer’s Disease Research, Ramat-Gan, Israel 5 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 901, room 315, Ramat-Gan 5290000, Israel