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Evolutionary plasticity of insect’s nuclear receptors


Nuclear receptors are ligand-dependent (hormone, fatty acid) gene regulators. They establish a direct link between the genome and the extracellular environment, acting both during transcription and signalisation. These animal-specific proteins play essential roles in the control of metabolism and development. The study of their evolutionary plasticity helps to understand fundamental problems such as: ligand-receptor relationships, coevolution between interacting proteins and phenotypic plasticity. These issues have important applications for pharmacology, endocrine disruptors studies and the struggle against invertebrate pests. We address these questions with insects, because they offer two of the best model species for genetic analysis (Drosophila and Tribolium). Furthermore, the complete set of nuclear receptors is about only 20 genes in insects, against 50-70 in vertebrates and >260 in nematodes (Laudet and Bonneton, 2005).

About one-third of extant insect’s species belong to the super-order Mecopterida, which includes Diptera (flies, mosquitoes) and Lepidoptera (moths, butterflies). The emergence of this group, around 300 MYA (Permian), was characterised by a genome-wide acceleration of the evolutionary rate. We have discovered that five nuclear receptors underwent a higher acceleration, when compared to other genes. This overacceleration affected ECR, USP, HR3, E75 and HR4, all acting during the early ecdysone response that controls moulting and metamorphosis. Our hypothesis is that, within this developmental network, coevolution allowed the conservation of vital protein-protein interactions (Bonneton et al., 2003, 2006, 2007).

In order to understand the molecular mechanisms of this coevolution, we are comparing ECR and USP (the heterodimer ECR-USP is the ecdysone receptor) between a Mecopterida, the fruitfly Drosophila melanogaster, and a Coleoptera, the red flour beetle Tribolium castaneum. We have chosen a Coleoptera because this order (25% of animal species) is the sister group to Mecopterida and did not experience a similar genome-wide acceleration. Tribolium, an important pest for stored grains and flours all around the world, is also becoming the third best model organism for genetic and developmental biology, after Drosophila and C. elegans. Its genome has been sequence and we have identified and annotated its 21 nuclear receptors (Tribolium annotation consortium, 2007; Bonneton et al., 2007). The ECR-USP heterodimer constitutes the ecdysone receptor among all arthropods. The Mecopterida overacceleration modified the ligand binding pocket of USP and the dimerisation surface of both proteins.

The 3D structure of the Tribolium heterodimer ECR-USP has revealed an original conformation with a true orphan USP lacking a pocket for ligand binding. Contrary to Mecopterida, where USP has a large pocket able to bind a (yet unknown) ligand, it seems that, in most insects, the activation of USP is independent of ligand binding (Iwema et al., 2007). This is intriguing since USP, like its vertebrate homolog RXR, which activity depends on fatty acid binding, is an essential partner for many other nuclear receptors. Furthermore, the structural and evolutionary analysis showed that the Mecopterida ECR-USP dimerisation surface is new and larger, when compared to other insects. This result suggests that coevolution between ECR and USP shaped adaptative changes inside the zone of interaction (Iwema et al., in preparation).

The consequences of Mecopterida acceleration on the coevolution between nuclear receptors of the ecdysone cascade constitute a good model to understand the molecular adaptations that can occur within the networks that regulate development.

References :

  • Bonneton F., Zelus D., Iwema T., Robinson-Rechavi M. and Laudet V. Rapid divergence of the ecdysone receptor in Diptera and Lepidoptera suggests coevolution between ECR and USP-RXR. Molecular Biology and Evolution, 2003, 20(4): 541-553.
  • Bonneton F., Brunet F.G., Kathirithamby J. and Laudet V. The rapid divergence of the ecdysone receptor is a synapomorphy for Mecopterida that clarifies the Strepsiptera problem. Insect Molecular Biology, 2006, 15(3) : 351- 362.
  • Bonneton F., Chaumot A. and Laudet V. Annotation of Tribolium nuclear receptors reveals an evolutionary overacceleration of a network controlling the ecdysone cascade. Insect Biochemistry and Molecular Biology, 2008, 38 : 416-429.
  • Iwema T., Billas I.M.L, Beck Y., Bonneton F., Nierengarten H., Chaumot A., Richards G., Laudet V. and Moras D. Structural and functional characterization of a novel type of ligand-independent RXR-USP. EMBO Journal, 2007, 26(16):3770-82.
  • Iwema T., Chaumot A., Studer R.A., Robinson-Rechavi M., Billas I.M.L, Moras D., Laudet V. and Bonneton F. Structural and Evolutionary innovation of the heterodimerisation interface between USP and the Ecdysone Receptor ECR in insects. Molecular Biology and Evolution, 2009, 26(4): 753-768.
  • Laudet V. and Bonneton F.. Evolution of nuclear hormone receptors in insects. Comprehensive Molecular Insect Science, 2005, edited by L. I. Gilbert, K. Iatrou and S. Gill, Elsevier, vol.3 : 287-318.
  • Tribolium Genome Sequencing Consortium. The genome of the model beetle and pest Tribolium castaneum. Nature, 2008, 452 : 949-955.