The LH/CG receptor activates canonical signaling pathway when expressed in Drosophila

• The gonadotropin receptors evolved in vertebrates but not in invertebrates.
• The human LH/CG receptor can function when expressed in Drosophila.
• The active gonadotropin receptor couples to the PKA/CREB pathway in the fly.
• The factors required for GPCR function in different animal phyla are conserved.

G-protein coupled receptors (GPCRs) and their ligands provide precise tissue regulation and are therefore often restricted to specific animal phyla. For example, the gonadotropins and their receptors are crucial for vertebrate reproduction but absent from invertebrates. In mammals, LHR mainly couples to the PKA signaling pathway, and CREB is the major transcription factor of this pathway. Here we present the results of expressing elements of the human gonadotropin system in Drosophila. Specifically, we generated transgenic Drosophila expressing the human LH/CG receptor (denoted as LHR), a constitutively active form of LHR, and an hCG analog. We demonstrate activation-dependent signaling by LHR to direct Drosophila phenotypes including lethality and specific midline defects; these phenotypes were due to LHR activation of PKA/CREB pathway activity. That the LHR can act in an invertebrate demonstrates the conservation of factors required for GPCR function among phylogenetically distant organisms. This novel gonadotropin model may assist the identification of new modulators of mammalian fertility by exploiting the powerful genetic and pharmacological tools available in Drosophila.