Ancestral glycoprotein hormone and its cognate receptor present in primitive chordate ascidian: Molecular identification and functional characterization

Yang, Likun; Zhang, Jin; Liu, Di; Han, Tong-Ye; Qin, Qi-Shu; Wang, Anqi; Dong, Bo

doi:10.1016/j.ijbiomac.2022.12.297

Cited by 7 publications

(14 citation statements)

References 48 publications

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“…We show that C. elegans GPLA-1/GPA2 and GPLB-1/GPB5 are cognate ligands of FSHR-1 in vivo and are able to functionally activate this receptor in vitro . Our results indicate that FSHR-1 has basal receptor activity, like other thyrostimulin receptors 28,29,76– 78 . Previous work identified a sequence motif in the third intracellular loop of FSHR-1 that is likely responsible for ligand-independent signaling 49 .…”

Section: Discussionmentioning

confidence: 54%

“…Phylogenetic analyses show a clear conservation of thyrostimulin GPA2 and GPB5 polypeptides across Protostomia and Deuterostomia, but their physiological roles remain elusive [7][8][9]14,26,29,46 . In invertebrates, GPA2/GPB5 orthologs have only been functionally characterized in arthropods 12,[38][39][40] .…”

Section: Discussionmentioning

confidence: 99%

“…However, thyrostimulin GPB5 polypeptides lack the seatbelt structure 3,9,81 , and whether heterodimerization is required for GPA2/GPB5 signaling is debated. Moreover, differences in the expression patterns of GPA2 and GPB5, both in vertebrates and invertebrates, suggest that the two subunits may have monomeric or homodimeric functions 21,25,27,29,38,82 . These findings have raised the question as to what the ancestral configuration of GPA2 and GPB5 hormones might have been and whether each subunit may also signal independently.…”

Section: Discussionmentioning

confidence: 99%

“…Like TSH, GPA2/GPB5 increases thyroid hormone secretion in rats and, based on its TSHR-and thyroid-stimulating activity, was named thyrostimulin 10 . Later studies in basal vertebrates, urochordates, cephalochordates, and insects revealed that the interaction of thyrostimulin with TSHR orthologs is widely conserved 14,23,[26][27][28][29] . Glycoprotein hormone receptors belong to a subfamily of leucine-rich repeat containing G protein-coupled receptors (LGRs) that are conserved across divergent animal phyla 7,8,30,31 .…”

Section: Introductionmentioning

confidence: 99%

“…Glycoprotein hormone receptors belong to a subfamily of leucine-rich repeat containing G protein-coupled receptors (LGRs) that are conserved across divergent animal phyla 7,8,30,31 . Thyrostimulin orthologs were found to activate LGRs related to TSHRs in lampreys, tunicates, Amphioxus, the fruit fly Drosophila melanogaster and the mosquito Aedes aegypti 14,23,[26][27][28][29] , indicating that the evolutionary origin of this glycoprotein hormone-receptor system dates back to a common ancestor of bilaterian animals.…”

Section: Introductionmentioning

confidence: 99%

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An ancient thyrostimulin-like neuroendocrine pathway regulates growth inCaenorhabditis elegans

Kenis

Istiban

Damme

et al. 2023

Preprint

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In vertebrates, thyrostimulin is a highly conserved glycoprotein hormone that, besides thyroid stimulating hormone (TSH), is a potent ligand of the TSH receptor. Thyrostimulin is considered the most ancestral glycoprotein hormone and orthologs of its subunits, GPA2 and GPB5, are widely conserved across vertebrate and invertebrate animals. Unlike TSH, however, the functions of the thyrostimulin neuroendocrine system remain largely unexplored. Here, we identify a functional thyrostimulin-like signaling system in Caenorhabditis elegans. We show that orthologs of GPA2 and GPB5, together with thyrotropin-releasing hormone (TRH) related neuropeptides, constitute a neuroendocrine pathway that promotes growth in C. elegans. GPA2/GPB5 signaling is required for normal body size and acts through activation of the glycoprotein hormone receptor ortholog FSHR-1. C. elegans GPA2 and GPB5 increase cAMP signaling by FSHR-1 in vitro. Both subunits are expressed in enteric neurons and promote growth by signaling to their receptor in glial cells and the intestine. Impaired GPA2/GPB5 signaling causes bloating of the intestinal lumen. In addition, mutants lacking thyrostimulin-like signaling are defective in defecation behavior. Our study suggests that the thyrostimulin GPA2/GPB5 pathway is an ancient enteric neuroendocrine system that regulates intestinal function in ecdysozoans, and may ancestrally have been involved in the control of organismal growth.

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