Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction

Yuling Feng; Nayeli Escudero Castelán; Mohammed Akhter Hossain; Hongkang Wu; Hidekazu Katayama; Stuart J. Smith; Scott F. Cummins; Masatoshi Mita; Ross A. D. Bathgate; Maurice R. Elphick

doi:10.1186/s12915-025-02158-2

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Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction

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Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction

Yuling Feng, Nayeli Escudero Castelán, Mohammed Akhter Hossain, Hongkang Wu, Hidekazu Katayama, Stuart J. Smith, Scott F. Cummins, Masatoshi Mita, Ross A. D. Bathgate and Maurice R. Elphick

BMC Biology, Vol.23(1), pp.1-24

2025

DOI: https://doi.org/10.1186/s12915-025-02158-2

PMCID: PMC11863921

PMID: 40001176

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Abstract

relaxin

starfish

receptor

reproduction

evolution

Background Relaxins are a family of peptides that regulate reproductive physiology in vertebrates. Evidence that this is an evolutionarily ancient role of relaxins has been provided by the discovery of two relaxin-like gonad-stimulating peptides (RGP1 and RGP2) that trigger spawning in starfish. The main aim of this study was to identify the receptor(s) that mediate(s) the effects of RGP1 and RGP2 in starfish. Results Here we show that RGP1 and RGP2 belong to a family of peptides that include vertebrate relaxins, Drosophila insulin-like peptide 8 (Dilp8), and other relaxin-like peptides in several protostome taxa. An ortholog of the human relaxin receptors RXFP1 and RXFP2 and the Drosophila receptor LGR3 was identified in starfish (RXFP/LGR3). In Drosophila, but not in humans and other vertebrates, there is a paralog of LGR3 known as LGR4, and here an LGR4-type receptor was also identified in starfish. In vitro pharmacological experiments revealed that both RGP1 and RGP2 act as ligands for RXFP/LGR3 in the starfish Acanthaster cf. solaris and Asterias rubens, but neither peptide acts as a ligand for LGR4 in these species. Conclusions Discovery of the RXFP/LGR3-type receptor for RGP1 and RGP2 in starfish provides a new insight into the evolution of relaxin-type signaling as a regulator of reproductive processes. Furthermore, our findings indicate that RXFP/LGR3-type receptors have been lost in several phyla, including urochordates, mollusks, bryozoans, platyhelminthes, and nematodes.

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Title: Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction
Authors: Yuling Feng - Queen Mary University of London
Nayeli Escudero Castelán - Queen Mary University of London
Mohammed Akhter Hossain - The University of Melbourne
Hongkang Wu - Florey Institute of Neuroscience and Mental Health
Hidekazu Katayama - Teikyo University
Stuart J. Smith - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Scott F. Cummins - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Masatoshi Mita - SHOWA Medical University
Ross A. D. Bathgate (Corresponding Author) - Florey Institute of Neuroscience and Mental Health
Maurice R. Elphick (Corresponding Author) - Queen Mary University of London
Publication details: BMC Biology, Vol.23(1), pp.1-24
Publisher: BioMed Central Ltd.
Date published: 2025
DOI: 10.1186/s12915-025-02158-2
ISSN: 1741-7007
PMID: 40001176; PMC11863921
Copyright note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Data Availability: All datasets generated or analysed during this study are included in this published article and its supplementary additional files.
Grants: GPCR Targeted Therapeutics, 1135837, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Grant note: The research reported in this paper was supported by the China Scholarship Council (studentship awarded to YF), the Biotechnology and Biological Sciences Research Council, UK (grant BB/X001024/1 awarded to MRE), and the Victorian Government’s Operational Infrastructure Support Program and JSPS KAKENHI grants awarded to M.M. (JP19K06747) and H.K. (JP18K05113).
Organisation Unit: School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 991108102902621
Output Type: Journal article

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