Ambulacrarian insulin-related peptides and their putative receptors suggest how insulin and similar peptides may have evolved from insulin-like growth factor

Abstract

Background Some insulin/IGF-related peptides (irps) stimulate a receptor tyrosine kinase (RTK) that transfers the extracellular hormonal signal into an intracellular response. Other irps, such as relaxin, do not use an RTK, but a G-protein coupled receptor (GPCR). This is unusual since evolutionarily related hormones typically either use the same or paralogous receptors. In arthropods three different irps, i.e. arthropod IGF, gonadulin and Drosophila insulin-like peptide 7 (dilp7), likely evolved from a gene triplication, as in several species genes encoding these three peptides are located next to one another on the same chromosomal fragment. These arthropod irps have homologs in vertebrates, suggesting that the initial gene triplication was perhaps already present in the last common ancestor of deuterostomes and protostomes. It would be interesting to know whether this is indeed so and how insulin might be related to this trio of irps. Methodology Genes encoding irps as well as their putative receptors were identified in genomes and transcriptomes from echinoderms and hemichordates. Results A similar triplet of genes coding for irps also occurs in some ambulacrarians. Two of these are orthologs of arthropod IGF and dilp7 and the third is likely a gonadulin ortholog. In echinoderms, two novel irps emerged, gonad stimulating substance (GSS) and multinsulin, likely from gene duplications of the IGF and dilp7-like genes respectively. The structures of GSS diverged considerably from IGF, which would suggest they use different receptors from IGF, but no novel irp receptors evolved. If IGF and GSS use different receptors, and the evolution of GSS from a gene duplication of IGF is not associated with the appearance of a novel receptor, while irps are known to use two different types of receptors, the ancestor of GSS and IGF might have acted on both types of receptors while one or both of its descendants act on only one. There are three ambulacrarian GPCRs that have amino acid sequences suggestive of being irp GPCRs, two of these are orthologs of the gonadulin and dilp7 receptors. This suggests that the third might be an IGF receptor, and that by deduction, GSS only acts on the RTK. The evolution of GSS from IGF may represent a pattern, where IGF gene duplications lead to novel genes coding for shorter peptides that activate an RTK. It is likely this is how insulin and the insect neuroendocrine irps evolved independently from IGF. Conclusion The local gene triplication described from arthropods that yielded three genes encoding irps was already present in the last common ancestor of protostomes and deuterostomes. It seems plausible that irps, such as those produced by neuroendocrine cells in the brain of insects and echinoderm GSS evolved independently from IGF and, thus, are not true orthologs, but the result of convergent evolution.

CRISPR/Cas9-mediated mutation on an insulin-like peptide encoding gene affects the growth of the ridgetail white prawn Exopalaemon carinicauda

“…(c) Conserved functional features. As one of the most important hormone growth factors, the growth-regulatory role of the insulin superfamily has been demonstrated in a variety of animals ( 8 , 22 , 54 ). In this study, the apparent growth-inhibitory phenotypes by both CRISPR/Cas9 and RNAi approaches suggested that EcILP was involved in the growth of E. carinicauda .…”

“…and ILP7 in T. castaneum ( 10 ). The emergence of the ILP7 is thought to be traced to a more ancient common ancestor of deuterostomes and protostomes ( 8 , 10 , 15 ). This ancient evolutionary position implies that DILP7/relaxin-like ILP may have more important and broader functions ( 15 ).…”

“…It is involved in controlling many aspects of life, such as growth, metabolism, reproduction, lifespan, resistance to stress conditions and immune activity (3)(4)(5). There are three major subgroups in this superfamily, including vertebrate insulin, insulin-like growth factors (IGFs) and protostomian insulin-like peptides (ILPs); there are also some other small subgroups, such as vertebrate relaxins and crustacean insulin-like androgenic gland (IAG) (6)(7)(8). Among protostomian, a large number of ILPs have been identified since the first ILP was discovered in Bombyx mori (silkworm) in 1984, known as bombyxin (9).…”

Insulin and Memory in Invertebrates

“…In addition to binding to the receptor tyrosine kinase InR, Dilps can also interact with G protein-coupled receptors. For example, Dilp7 and Dilp8 activate the relaxin receptor-like LGR4 and LGR3, respectively (Colombani et al, 2015 ; Gontijo and Garelli, 2018 ; Mita, 2019 ; Veenstra et al, 2021 ; Veenstra, 2021 ). Moreover, Dilp3 functions in intermediate-term memory of aversive olfactory conditioning (Tanabe et al, 2017 ).…”

Different neuroendocrine cell types in thepars intercerebralisofPeriplaneta americanaproduce their own specific IGF-related peptides

“…Two of these genes are likely the ascendants of IGF for one and vertebrate relaxin, arthropod gonadulin and ambulacrarian octinsulin for the second, while the third gave rise to the Drosophila insulin-like peptide 7 (dilp7) orthologs, that are found in insects and other protostomes as well as ambulacrarians. The ambulacrarian data suggests that other, smaller hormones, like insulin, the insect neuroendocrine insulin-like peptides, and the ambulacrarian gonad stimulating substances may have evolved independently from somatomedin and hence are not direct orthologs of one another, but rather the products of convergent evolution (Veenstra, 2020(Veenstra, , 2021a. The term insulin-like peptide and its acronym ilp does not differentiate between these smaller peptides and the triplet consisting of IGF, gonadulin and the dilp7 orthologs.…”