Dilp8-Lgr3 pathway: A relaxin-like pathway controlling developmental transitions

Abstract

The capacity to replace damaged tissues is a common characteristic in most metazoans. However, the regenerative competence of different tissues can vary significantly between animal groups and their life cycle stages. In arthropods, the ability to regenerate external structures is limited to the growth phases of their life cycles and is tightly coordinated with molting due to growth restrictions imposed by the hard exoskeleton. Accordingly, crabs, which can grow and molt after reaching maturity, can regenerate legs throughout their life, but insects lose this capacity as they reach adulthood and stop growing. The potential fitness impairment that results from the inability to regenerate injured structures is bypassed in insects by tissue-damaged triggered mechanisms that have evolved to extend the growth-competent period and provide extra time for regeneration. The molecular and cellular players mediating this coordination between tissue growth and developmental timing have been recently discovered in Drosophila. The insulin/relaxin-like peptide, Drosophila insulin-like peptide 8 (Dilp8), was identified as a factor communicating abnormal growth status of Drosophila larval imaginal discs to the neuroendocrine centers that control the timing of the onset of metamorphosis. We found that dilp8 is highly and specifically expressed in imaginal discs in response to a variety of growth alterations and requires a neuronal relaxin receptor for this function, the Leucine rich repeat containing G protein coupled receptor, Lgr3. Imaginal discderived Dilp8 acts on four central nervous system Lgr3- positive neurons to activate cyclic-AMP signaling. This delays the induction of the transcription of enzymes in the ecdysone synthesis cascade and causes a reduction in ecdysone hormone production, which leads to an extension of the larval growth period and a simultaneous restriction of the growth rates of healthy imaginal tissues, promoting the generation of proportionate individuals. Similarities between the Dilp8-Lgr3 pathway controlling larval-to-pupal transitions and the hypothalamic-pituitary axis in vertebrates suggest that relaxins might be part of an ancient stress-responsive pathway coordinating animal growth and maturation timing. Analysis of dilp8 expression pattern suggests that the Dilp8-Lgr3 pathway might have other functions at different life history stages. Dilp8 is expressed in the ovary and in multiple pulses close to the ecdysone surges that control major developmental transitions. The highest expression is reached at the larval to pupal transition, when the larva shortens and hardens its cuticle to acquire a typical barrel shape. Interestingly, both dilp8 and Lgr3 mutants show defective puparium contraction. Recent data show that dilp8 is expressed in the epidermis and received by a population of Lgr3+ neurons different from those involved in growth coordination. Our results indicate that the Dilp8-Lgr3 pathway has multiple conserved roles in insect development which involve parallel neuroendocrine circuits.