Neural Signaling and Circuit Plasticity Group, Department of Biology, KU Leuven, Leuven, Belgium.
Functional Genomics and Proteomics Group, Department of Biology, KU Leuven, Leuven, Belgium.
Front Endocrinol (Lausanne). 2023 Jun 20;14:1200407. doi: 10.3389/fendo.2023.1200407. eCollection 2023.
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 . We show that orthologs of GPA2 and GPB5, together with thyrotropin-releasing hormone (TRH) related neuropeptides, constitute a neuroendocrine pathway that promotes growth in . GPA2/GPB5 signaling is required for normal body size and acts through activation of the glycoprotein hormone receptor ortholog FSHR-1. GPA2 and GPB5 increase cAMP signaling by FSHR-1 . 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.
在脊椎动物中，促甲状腺激素释放素是一种高度保守的糖蛋白激素，除了促甲状腺激素（TSH）之外，它还是 TSH 受体的有效配体。促甲状腺激素释放素被认为是最古老的糖蛋白激素，其亚基 GPA2 和 GPB5 的同源物在脊椎动物和无脊椎动物中广泛保守。然而，与 TSH 不同，促甲状腺激素释放素神经内分泌系统的功能在很大程度上仍未得到探索。在这里，我们在 中鉴定出一种功能性的促甲状腺激素样信号系统。我们表明，GPA2 和 GPB5 的同源物与促甲状腺激素释放激素（TRH）相关神经肽一起构成了一个促进生长的神经内分泌途径。GPA2/GPB5 信号对于正常的体型是必需的，并且通过激活糖蛋白激素受体同源物 FSHR-1 发挥作用。GPA2 和 GPB5 通过 FSHR-1 增加 cAMP 信号。这两个亚基都在肠神经元中表达，并通过在神经胶质细胞和肠道中向其受体发出信号来促进生长。GPA2/GPB5 信号的受损导致肠腔的膨胀。此外，缺乏促甲状腺激素样信号的突变体显示出增加的排便周期。我们的研究表明，促甲状腺激素释放素 GPA2/GPB5 途径是一种古老的肠神经内分泌系统，它调节节肢动物的肠道功能，并且可能在起源上参与了对生物体生长的控制。
