Three-tier regulation of cell number plasticity by neurotrophins and Tolls in $\textit{Drosophila}$

Cell number plasticity is coupled to circuitry in the nervous system, adjusting cell mass to functional requirements. In mammals, this is achieved by neurotrophin (NT) ligands, which promote cell survival via their Trk and p75$^{NTR }$ receptors and cell death via p75$^{NTR }$ and Sortilin. $\textit{Drosophila}$ NTs (DNTs) bind Toll receptors instead to promote neuronal survival, but whether they can also regulate cell death is unknown. In this study, we show that DNTs and Tolls can switch from promoting cell survival to death in the central nervous system (CNS) via a three-tier mechanism. First, DNT cleavage patterns result in alternative signaling outcomes. Second, different Tolls can preferentially promote cell survival or death. Third, distinct adaptors downstream of Tolls can drive either apoptosis or cell survival. Toll-6 promotes cell survival via MyD88-NF-κB and cell death via Wek-Sarm-JNK. The distribution of adaptors changes in space and time and may segregate to distinct neural circuits. This novel mechanism for CNS cell plasticity may operate in wider contexts.This work was funded by the Wellcome Trust grant 094175/Z/10/Z to A. Hidalgo and N.J. Gay, the Biotechnology and Biological Sciences Research Council grant BB/L008343/1 to A. Hidalgo, the Medical Research Council Career Establishment Grant to A. Hidalgo, the Wellcome Trust grant 088583/Z/09/Z to A. Hidalgo, a Marie Skłodowska Curie-Actions Intra-European Fellowship (Kon-TikiGENET) to M. Losada-Perez, and a Biotechnology and Biological Sciences Research Council Midlands Integrative Biosciences Training Partnership studentship to N. Anthoney