Thompson Christopher K, Cline Hollis T
Department of Molecular and Cellular Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92039.
Department of Molecular and Cellular Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92039
J Neurosci. 2016 Oct 5;36(40):10356-10375. doi: 10.1523/JNEUROSCI.4147-15.2016.
Thyroid hormone (TH) regulates many cellular events underlying perinatal brain development in vertebrates. Whether and how TH regulates brain development when neural circuits are first forming is less clear. Furthermore, although the molecular mechanisms that impose spatiotemporal constraints on TH action in the brain have been described, the effects of local TH signaling are poorly understood. We determined the effects of manipulating TH signaling on development of the optic tectum in stage 46-49 Xenopus laevis tadpoles. Global TH treatment caused large-scale morphological effects in tadpoles, including changes in brain morphology and increased tectal cell proliferation. Either increasing or decreasing endogenous TH signaling in tectum, by combining targeted DIO3 knockdown and methimazole, led to corresponding changes in tectal cell proliferation. Local increases in TH, accomplished by injecting suspensions of tri-iodothyronine (T) in coconut oil into the midbrain ventricle or into the eye, selectively increased tectal or retinal cell proliferation, respectively. In vivo time-lapse imaging demonstrated that local TH first increased tectal progenitor cell proliferation, expanding the progenitor pool, and subsequently increased neuronal differentiation. Local T also dramatically increased dendritic arbor growth in neurons that had already reached a growth plateau. The time-lapse data indicate that the same cells are differentially sensitive to T at different time points. Finally, TH increased expression of genes pertaining to proliferation and neuronal differentiation. These experiments indicate that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting cell proliferation and differentiation and by acting on neurons to increase dendritic arbor elaboration.
Thyroid hormone (TH) is a critical regulator of perinatal brain development in vertebrates. Abnormal TH signaling in early pregnancy is associated with significant cognitive deficits in humans; however, it is difficult to probe the function of TH in early brain development in mammals because of the inaccessibility of the fetal brain in the uterine environment and the challenge of disambiguating maternal versus fetal contributions of TH. The external development of tadpoles allows manipulation and direct observation of the molecular and cellular mechanisms underlying TH's effects on brain development in ways not possible in mammals. We find that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting neural progenitor cell proliferation and differentiation and by acting on neurons to enhance dendritic arbor elaboration.
甲状腺激素（TH）调节脊椎动物围产期大脑发育过程中的许多细胞活动。在神经回路刚开始形成时，TH是否以及如何调节大脑发育尚不清楚。此外，尽管已经描述了对大脑中TH作用施加时空限制的分子机制，但对局部TH信号传导的影响却知之甚少。我们确定了操纵TH信号传导对46 - 49期非洲爪蟾蝌蚪视顶盖发育的影响。全身性TH处理在蝌蚪中引起了大规模的形态学效应，包括脑形态的变化和顶盖细胞增殖的增加。通过联合靶向DIO3敲低和甲巯咪唑来增加或减少顶盖中的内源性TH信号传导，均导致顶盖细胞增殖发生相应变化。通过将三碘甲状腺原氨酸（T）悬浮液注射到中脑室或眼睛中实现局部TH增加，分别选择性地增加了顶盖或视网膜细胞增殖。体内延时成像表明，局部TH首先增加顶盖祖细胞增殖，扩大祖细胞池，随后增加神经元分化。局部T还显著增加了已经达到生长平台期的神经元的树突分支生长。延时数据表明，相同的细胞在不同时间点对T的敏感性不同。最后，TH增加了与增殖和神经元分化相关的基因表达。这些实验表明，内源性TH通过影响细胞增殖和分化以及作用于神经元以增加树突分支细化，在与回路组装相关的发育阶段局部调节神经发生。
甲状腺激素（TH）是脊椎动物围产期大脑发育的关键调节因子。妊娠早期TH信号异常与人类显著的认知缺陷有关；然而，由于子宫环境中胎儿大脑难以触及以及区分母体与胎儿对TH的贡献具有挑战性，因此难以探究TH在哺乳动物早期大脑发育中的功能。蝌蚪的外部发育使得以哺乳动物无法实现的方式操纵和直接观察TH对大脑发育影响的分子和细胞机制成为可能。我们发现，内源性TH通过影响神经祖细胞增殖和分化以及作用于神经元以增强树突分支细化，在与回路组装相关的发育阶段局部调节神经发生。
