Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
Department of Oncology Bioinformatics, Genentech, South San Francisco, CA, USA.
Nat Metab. 2023 Dec;5(12):2094-2110. doi: 10.1038/s42255-023-00937-1. Epub 2023 Dec 20.
The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes. We discover two thyrocyte subtypes in mouse and human thyroids, identified in single-cell analyses by different levels of metabolic activity and Notch signalling. Therapeutic antibody blockade of Notch in adult mice inhibits a thyrocyte-specific transcriptional program and induces thyrocyte defects due to decreased mitochondrial activity and ROS production. Thus, disrupting Notch signalling in adult mice causes hypothyroidism, characterized by reduced levels of circulating thyroid hormone and dysregulation of whole-body thermoregulation. Inducible genetic deletion of Notch1 and 2 in thyrocytes phenocopies this antibody-induced hypothyroidism, establishing a direct role for Notch in adult murine thyrocytes. We confirm that hypothyroidism is enriched in children with Alagille syndrome, a genetic disorder marked by Notch mutations, suggesting that these findings translate to humans.
甲状腺作为一个顶端内分泌器官，控制着生长、分化和代谢，甲状腺疾病是最常见的内分泌紊乱。然而，对于控制甲状腺的细胞组成和信号的高分辨率视图一直缺乏。在这里，我们表明 Notch 信号通过一组甲状腺细胞中线粒体为基础的机制来控制成年哺乳动物的体内平衡和体温调节。我们在小鼠和人类甲状腺中发现了两种甲状腺细胞亚型，通过单细胞分析发现，它们的代谢活性和 Notch 信号水平不同。在成年小鼠中，针对 Notch 的治疗性抗体阻断会抑制甲状腺细胞特异性转录程序，并由于线粒体活性降低和 ROS 产生而导致甲状腺细胞缺陷。因此，在成年小鼠中破坏 Notch 信号会导致甲状腺功能减退，其特征是循环甲状腺激素水平降低和全身体温调节失调。在甲状腺细胞中诱导性遗传缺失 Notch1 和 2 可模拟这种抗体诱导的甲状腺功能减退症，从而确立了 Notch 在成年小鼠甲状腺细胞中的直接作用。我们证实，在 Alagille 综合征（一种以 Notch 突变为特征的遗传疾病）患儿中，甲状腺功能减退症更为丰富，这表明这些发现适用于人类。
