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

Abstract

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.

Sex-specific regulation of Lgr3 in Drosophila neurons

“…This homology has led to the proposal that insulin-like peptides, especially Dilp8, may function as ligands for Lgr3 in Drosophila (39). Dilp8 has been implicated in the regulation of developmental timing and growth in the larva (40,41), and Lgr3 has recently been found to be necessary for this Dilp8 function (42)(43)(44). Lgr3 mutants appear to develop similarly to dilp8 mutants and prevent effects of Dilp8 overexpression, and some evidence has been found for direct interaction between them (44; but see ref.…”

“…Lgr3 mutants appear to develop similarly to dilp8 mutants and prevent effects of Dilp8 overexpression, and some evidence has been found for direct interaction between them (44; but see ref. 43).…”

The Fruit Fly, Drosophila melanogaster: The Making of a Model (Part I)

“…Each instar stage is regulated by the level of PTTH that rises to control the release of ecdysone allowing larvae to grow [9]. PTTH is released from neurosecretory cells in the brain, a process that is remotely controlled by growth of the larval organs and imaginal discs, sac-like structures of monoepithelial cells that become organs after metamorphosis, with the release of dilp8, a member of the secreted insulin-like peptide family, in a negative feed-back loop that controls PTTH production [10][11][12]. PTTH stimulates the release Drosophila melanogaster -Model for Recent Advances in Genetics and Therapeuticsof the molting hormone ecdysone from the prothoracic glands into the hemolymph causing the formation of a new cuticle (exoskeleton).…”

Des insulines pour orchestrer la croissance

“…Lgr3 est pré-sent dans une sous-population de neurones dont deux seulement sont requis pour l'induction du retard déve-loppemental par Dilp8 (appelés growth coordinating Lgr3-positive neurons ou neurones GCL). Les neurones GCL semblent contrôler les niveaux d'ecdysone par une interaction physique avec des neurones intermédiaires à PTTH (prothoracicotropic hormone) 3 qui projettent leurs axones sur la glande en anneau, le site de production de l'ecdysone [20][21][22][23][24]. 2 Le cycle de vie de la drosophile se divise en quatre phases durant lesquelles les individus prennent des morphologies trè s diffé rentes : l'oeuf (stade embryonnaire), la larve (stade larvaire), la pupe (stade pupal) et l'imago (stade adulte).…”

“…L'expression de lgr3 n'étant pas détectable au sein des disques imaginaux [20,21], Dilp8 pourrait agir de façon autonome via un autre récepteur. Un test de capture ligand-récepteur suivi d'une analyse par spectrométrie de masse a montré que Dilp8 peut se lier in vitro au récepteur unique de l'insuline (InR) [21]. Dilp8 pourrait donc contrôler la croissance en se fixant à l'InR et en modulant par exemple la capacité des autres Dilp à activer la croissance des tissus imaginaux via ce récepteur.…”