Tieman Katherine, Heyland Andreas
Integrative Biology, University of Guelph, Guelph, ON, Canada.
Front Endocrinol (Lausanne). 2025 Aug 21;16:1648899. doi: 10.3389/fendo.2025.1648899. eCollection 2025.
Thyroid hormones (THs) are essential regulators of metabolism, homeostasis, and development in metazoans. The canonical genomic pathway involves THs binding to nuclear thyroid hormone receptors (NTHRs), which modulate gene expression in vertebrates. In contrast, non-genomic pathways involve THs interacting with membrane-bound or cytoplasmic receptors. One such pathway includes TH binding to the RGD-binding integrin dimer αVβ3, which activates the Mitogen-Activated Protein Kinase (MAPK) cascade, influencing cancer cell proliferation, metastasis, and angiogenesis. Both T4 and sulfated thyroid hormones (STHs) have been identified as actual and putative ligands in this pathway respectively. In the sea urchin , T4 and to a lesser extent T3 accelerate biomineralization-the formation of skeletal structures during embryonic and larval development-by modulating the activity of key transcription factors involved in this process. RGD peptides, potential ligands for the sea urchin integrin αPβG, can inhibit T4-induced effects, suggesting a role for integrin-mediated MAPK signaling (ERK1/2). This study examines whether STHs have developmental roles in sea urchin embryonic skeletogenesis and whether they bind to the αPβG integrin dimer , a TH receptor candidate in sea urchins. Our findings show that STHs, like T4, accelerate the onset of skeletogenesis and increase the frequency of ectopic spicule formation, particularly near ectodermal cells. Homology modeling indicates that the αPβG integrin binds both T4 and STHs with high affinity, whereas no strong binding was observed between TH metabolites and the NTHR in sea urchins. We conclude that STHs have a developmental function in sea urchin skeletogenesis, likely mediated by the αPβG integrin rather than the NTHR. This represents the first documented developmental role of STHs and highlights the importance of non-canonical TH signaling in invertebrate development, encouraging further exploration of TH pathways in non-chordate animals.
甲状腺激素（THs）是后生动物新陈代谢、体内平衡和发育的重要调节因子。经典的基因组途径涉及THs与核甲状腺激素受体（NTHRs）结合，从而调节脊椎动物的基因表达。相比之下，非基因组途径涉及THs与膜结合或细胞质受体相互作用。其中一条途径包括TH与RGD结合整合素二聚体αVβ3结合，激活丝裂原活化蛋白激酶（MAPK）级联反应，影响癌细胞的增殖、转移和血管生成。T4和硫酸化甲状腺激素（STHs）分别被确定为该途径中的实际和假定配体。在海胆中，T4以及程度较轻的T3通过调节参与这一过程的关键转录因子的活性，加速生物矿化——胚胎和幼虫发育过程中骨骼结构的形成。RGD肽是海胆整合素αPβG的潜在配体，可抑制T4诱导的效应，提示整合素介导的MAPK信号传导（ERK1/2）发挥了作用。本研究探讨了STHs在海胆胚胎骨骼发生中是否具有发育作用，以及它们是否与αPβG整合素二聚体结合，αPβG整合素二聚体是海胆中的一种TH受体候选物。我们的研究结果表明，STHs与T4一样，加速骨骼发生的起始，并增加异位骨针形成频率，尤其是在外胚层细胞附近。同源建模表明，αPβG整合素以高亲和力结合T4和STHs，而在海胆中未观察到TH代谢产物与NTHR之间有强结合。我们得出结论，STHs在海胆骨骼发生中具有发育功能，可能是由αPβG整合素而非NTHR介导的。这是首次记录的STHs的发育作用，并突出了非经典TH信号在无脊椎动物发育中的重要性，鼓励进一步探索非脊索动物中的TH途径。
