Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein, University of Lübeck and University of Kiel, Lübeck 23562, Germany.
Institute for Endocrinology and Diabetes, University of Lübeck and Universitätsklinikum Schleswig-Holstein Campus Lübeck, Center of Brain Behavior and Metabolism (CBBM), Ratzeburger Allee 160, 23562 Lübeck, Germany.
Development. 2023 Feb 1;150(3). doi: 10.1242/dev.201228. Epub 2023 Jan 30.
Thyroid hormone and its receptor TRα1 play an important role in brain development. Several animal models have been used to investigate this function, including mice heterozygous for the TRα1R384C mutation, which confers receptor-mediated hypothyroidism. These mice display abnormalities in several autonomic functions, which was partially attributed to a developmental defect in hypothalamic parvalbumin neurons. However, whether other cell types in the hypothalamus are similarly affected remains unknown. Here, we used single-nucleus RNA sequencing to obtain an unbiased view on the importance of TRα1 for hypothalamic development and cellular diversity. Our data show that defective TRα1 signaling has surprisingly little effect on the development of hypothalamic neuronal populations, but it heavily affects hypothalamic oligodendrocytes. Using selective reactivation of the mutant TRα1 during specific developmental periods, we find that early postnatal thyroid hormone action seems to be crucial for proper hypothalamic oligodendrocyte maturation. Taken together, our findings underline the well-known importance of postnatal thyroid health for brain development and provide an unbiased roadmap for the identification of cellular targets of TRα1 action in mouse hypothalamic development.
甲状腺激素及其受体 TRα1 在大脑发育中起着重要作用。已经使用了几种动物模型来研究这一功能，包括 TRα1R384C 突变杂合的小鼠，该突变赋予了受体介导的甲状腺功能减退症。这些小鼠表现出几种自主功能异常，部分归因于下丘脑颗粒蛋白神经元的发育缺陷。然而，下丘脑的其他细胞类型是否也受到类似的影响尚不清楚。在这里，我们使用单细胞 RNA 测序来获得对 TRα1 对下丘脑发育和细胞多样性的重要性的无偏观察。我们的数据表明，缺陷的 TRα1 信号传导对下丘脑神经元群体的发育几乎没有影响，但对下丘脑少突胶质细胞有很大影响。通过在特定的发育时期选择性地重新激活突变的 TRα1，我们发现新生儿后甲状腺激素的作用似乎对适当的下丘脑少突胶质细胞成熟至关重要。总之，我们的发现强调了新生儿期甲状腺健康对大脑发育的重要性，并为确定 TRα1 在小鼠下丘脑发育中的细胞作用靶点提供了无偏的路线图。
