Stepien Barbara K, Huttner Wieland B
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Front Endocrinol (Lausanne). 2019 Apr 3;10:209. doi: 10.3389/fendo.2019.00209. eCollection 2019.
Ever since the discovery of thyroid hormone deficiency as the primary cause of cretinism in the second half of the 19th century, the crucial role of thyroid hormone (TH) signaling in embryonic brain development has been established. However, the biological understanding of TH function in brain formation is far from complete, despite advances in treating thyroid function deficiency disorders. The pleiotropic nature of TH action makes it difficult to identify and study discrete roles of TH in various aspect of embryogenesis, including neurogenesis and brain maturation. These challenges notwithstanding, enormous progress has been achieved in understanding TH production and its regulation, their conversions and routes of entry into the developing mammalian brain. The endocrine environment has to adjust when an embryo ceases to rely solely on maternal source of hormones as its own thyroid gland develops and starts to produce endogenous TH. A number of mechanisms are in place to secure the proper delivery and action of TH with placenta, blood-brain interface, and choroid plexus as barriers of entry that need to selectively transport and modify these hormones thus controlling their active levels. Additionally, target cells also possess mechanisms to import, modify and bind TH to further fine-tune their action. A complex picture of a tightly regulated network of transport proteins, modifying enzymes, and receptors has emerged from the past studies. TH have been implicated in multiple processes related to brain formation in mammals-neuronal progenitor proliferation, neuronal migration, functional maturation, and survival-with their exact roles changing over developmental time. Given the plethora of effects thyroid hormones exert on various cell types at different developmental periods, the precise spatiotemporal regulation of their action is of crucial importance. In this review we summarize the current knowledge about TH delivery, conversions, and function in the developing mammalian brain. We also discuss their potential role in vertebrate brain evolution and offer future directions for research aimed at elucidating TH signaling in nervous system development.
自19世纪下半叶发现甲状腺激素缺乏是克汀病的主要病因以来，甲状腺激素（TH）信号在胚胎脑发育中的关键作用已得到确立。然而，尽管在治疗甲状腺功能缺乏症方面取得了进展，但对TH在脑形成中的功能的生物学理解仍远未完成。TH作用的多效性使得难以确定和研究TH在胚胎发生的各个方面（包括神经发生和脑成熟）中的离散作用。尽管存在这些挑战，但在理解TH的产生及其调节、它们的转化以及进入发育中的哺乳动物脑的途径方面已经取得了巨大进展。当胚胎不再仅仅依赖母体激素来源，而是随着自身甲状腺的发育并开始产生内源性TH时，内分泌环境必须进行调整。有多种机制来确保TH的适当递送和作用，胎盘、血脑界面和脉络丛作为进入的屏障，需要选择性地运输和修饰这些激素，从而控制它们的活性水平。此外，靶细胞也具有导入、修饰和结合TH以进一步微调其作用的机制。过去的研究已经揭示了一个由转运蛋白、修饰酶和受体组成的严格调控网络的复杂图景。TH与哺乳动物脑形成相关的多个过程有关——神经元祖细胞增殖、神经元迁移、功能成熟和存活——其确切作用随发育时间而变化。鉴于甲状腺激素在不同发育时期对各种细胞类型产生的大量影响，其作用的精确时空调节至关重要。在这篇综述中，我们总结了关于TH在发育中的哺乳动物脑中的递送、转化和功能的当前知识。我们还讨论了它们在脊椎动物脑进化中的潜在作用，并为旨在阐明神经系统发育中TH信号的研究提供了未来方向。
