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Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates

Ivell, Richard; Alhujaili, Waleed; Kohsaka, Tetsuya; Anand-Ivell, Ravinder


Richard Ivell

Waleed Alhujaili

Tetsuya Kohsaka


© 2020 Elsevier Inc. Although the insulin-like peptide hormone INSL3 and its cognate receptor RXFP2 (relaxin-family peptide receptor 2) have existed throughout chordate evolution, their physiological diversification appears to be linked closely with mammalian emergence and radiation. In contrast, they have been lost in birds and reptiles. Both hormone and receptor are expressed from autosomal genes which have maintained their synteny across vertebrate evolution. Whereas the INSL3 gene comprises only two exons closely linked to the JAK3 gene, RXFP2 is normally encoded by 18 exons. Both genes, however, are subject to alternative splicing to yield a variety of possibly inactive or antagonistic molecules. In mammals, the INSL3-RXFP2 dyad has maintained a probably primitive association with gametogenesis, seen also in fish, whereby INSL3 promotes the survival, growth and differentiation of male germ cells in the testis and follicle development in the ovary. In addition, however, the INSL3/RXFP2 system has adopted a typical ‘neohormone’ profile, essential for the promotion of internal fertilisation and viviparity; fetal INSL3 is essential for the first phase of testicular descent into a scrotum, and also appears to be associated with male phenotype, in particular horn and skeletal growth. Circulating INSL3 is produced exclusively by the mature testicular Leydig cells in male mammals and acts as a potent biomarker for testis development during fetal and pubertal development as well as in ageing. As such it can be used also to monitor seasonally breeding animals as well as to investigate environmental or lifestyle conditions affecting development. Nevertheless, most information about INSL3 and RXFP2 comes from a very limited selection of species; it will be especially useful to gain further information from a more diverse range of animals, especially those whose evolution has led them to express unusual reproductive phenotypes.


Ivell, R., Alhujaili, W., Kohsaka, T., & Anand-Ivell, R. (2020). Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates. General and Comparative Endocrinology, 299,

Journal Article Type Article
Acceptance Date Aug 8, 2020
Online Publication Date Aug 13, 2020
Publication Date Dec 1, 2020
Deposit Date Aug 19, 2020
Publicly Available Date Aug 14, 2021
Journal General and Comparative Endocrinology
Print ISSN 0016-6480
Electronic ISSN 1095-6840
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 299
Article Number 113583
Keywords Puberty, Neohormone, Testis descent, Horn growth, Spermatogenesis, Antral follicle growth
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