Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing

We thank C. Mirth, C. Ribeiro and A. Jacinto for their comments and suggestions; I. Miguel-Aliaga, A. Jacinto, P. Leopold, P. Domingos, C. Mirth, R. Teodoro, M. Dominguez, M.L. Vasconcelos, J.C. Yin and M. O'Connor, for reagents. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. A.M.G., F.H., A.M., A.R.M.D. and T.K. are supported by the FCT, under the FCT Investigator Programme and FCT fellowships SFRH/BPD/94112/2013, PD/BD/52421/2013, SFRH/BD/94931/2013 and SFRH/BPD/74313/2010, respectively. A.G. is supported by the CONICET and UNS, and Y.A.V. holds a CONICET fellowship. The work in the laboratory of A.M.G. is funded by the CEDOC and the European Commission FP7 (PCIG13-GA-2013-618847). A.G. thanks N.P. Rotstein and L.E. Politi for providing funds and space to develop a part of this project in their lab.How different organs in the body sense growth perturbations in distant tissues to coordinate their size during development is poorly understood. Here we mutate an invertebrate orphan relaxin receptor gene, the Drosophila Leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), and find body asymmetries similar to those found in insulin-like peptide 8 (dilp8) mutants, which fail to coordinate growth with developmental timing. Indeed, mutation or RNA intereference (RNAi) against Lgr3 suppresses the delay in pupariation induced by imaginal disc growth perturbation or ectopic Dilp8 expression. By tagging endogenous Lgr3 and performing cell type-specific RNAi, we map this Lgr3 activity to a new subset of CNS neurons, four of which are a pair of bilateral pars intercerebralis Lgr3-positive (PIL) neurons that respond specifically to ectopic Dilp8 by increasing cAMP-dependent signalling. Our work sheds new light on the function and evolution of relaxin receptors and reveals a novel neuroendocrine circuit responsive to growth aberrations.publishersversionpublishe