Ancestral glycoprotein hormone-receptor pathway controls growth in C. elegans

Abstract

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 show an increased defecation cycle period. 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.

Cell non-autonomous signaling through the conservedC. elegansglycopeptide hormone receptor FSHR-1 regulates cholinergic neurotransmission

“…While an interesting possibility, it is not the most parsimonious model of FSHR-1 function and is not consistent with the synaptic vesicle accumulation seen in cholinergic and, to a lesser extent, in GABAergic motor neurons, nor with the exacerbation of synaptic vesicle accumulation defects in both cholinergic and GABAergic rescue strains (Figure 2, Supplemental Figure 3, 7). Most importantly, we and others have been unable to detect significant fshr-1 expression in the dorsal or ventral nerve cords (Cho et al, 2007; Hammarlund et al, 2018; Kenis et al, 2023). If fshr-1 ultimately proves to be expressed at low levels in motor neurons, additional studies will be required to identify and describe cell type-specific FSHR-1 signaling pathways that could mediate cell autonomous effects.…”

“…In addition, we found that fshr-1 mutant animals have reduced body bending amplitude during crawling on agar (Figure 1C). The altered swimming and crawling behaviors were each rescued to wild type levels by expression of the fshr-1 genomic sequence and endogenous promoter using two independent lines (Cho et al, 2007; Kenis et al, 2023), demonstrating the specificity of the phenotype (Figure 1A-C). Additional high-resolution single-worm tracking experiments revealed reductions in head bending, locomotion speed, and foraging speed compared to wild type worms (Supplemental Figure 1), further supporting involvement of fshr-1 in neuromuscular regulation and motility.…”

“…Mammalian glycoprotein hormone receptors can act through several different signaling pathways depending on the cell type and context (Ulloa-Aguirre et al, 2018). Previous studies in C. elegans demonstrated that FSHR-1 acts upstream of genes encoding the Gα S protein GSA-1 and the adenylyl cyclase ACY-1 (Cho et al, 2007; Sieburth et al, 2007; Wang et al, 2023), and FSHR-1 can activate cAMP signaling when expressed in cultured mammalian cells (Kudo et al, 2000; Kenis et al, 2023). To assess the potential involvement of these downstream players in FSHR-1 modulation of cholinergic neuromuscular signaling, we used strains carrying gain-of-function ( gf ) GSA-1 and ACY-1 alleles that have been previously shown to promote muscle excitation (Charlie et al, 2006; Schade et al, 2005).…”

“…Second, our own and others’ expression data does support the potential for cell non-autonomous activity of fshr-1 in some other distal tissues. In addition to its expression in the intestine, fshr-1 expression appears in subsets of glial cells (all six IL socket glia, Supplemental Figure 8; Kenis et al 2023) and transcripts have been detected in head neurons, such as ASEL chemosensory neurons, as well as in CAN cells, DVB motor neurons in the defecation circuit, and PVW interneurons in the tail (Cho et al, 2007; Hammarlund et al, 2018; Kenis et al, 2023). Either glial cells or these neurons, may release neuropeptides or other molecules that act at a distance to impact neuromuscular function (Frakes et al, 2020; Wang and Bianchi, 2021).…”

“…Recent work implicated the GPLA-1/GPA2 and GPLB-1/GPB5 thyrostimulin-like subunits as FSHR-1 ligands in the regulation of body size (Kenis et al, 2023); other results demonstrated a similar role for GPLA-1 with FSHR-1 in controlling phenoptosis and growth but did not test GPLB-2 (Torzone et al, 2023; Wang et al, 2023). Our results add to the list of processes regulated by GPA2/GPB5 signaling in conjunction with FSHR-1.…”