Hatsukano Tetsu, Kurisu Junko, Fukumitsu Kansai, Fujishima Kazuto, Kengaku Mineko
Kengaku Group, Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto UniversityKyoto, Japan.
Kengaku Group, Graduate School of Biostudies, Kyoto UniversityKyoto, Japan.
Front Cell Neurosci. 2017 May 9;11:133. doi: 10.3389/fncel.2017.00133. eCollection 2017.
Thyroid hormone 3,3',5-Triiodo-L-thyronine (T3) is essential for proper brain development. Perinatal loss of T3 causes severe growth defects in neurons and glia, including strong inhibition of dendrite formation in Purkinje cells in the cerebellar cortex. Here we show that T3 promotes dendritic outgrowth of Purkinje cells through induction of peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. PGC-1α expression in Purkinje cells is upregulated during dendritic outgrowth in normal mice, while it is significantly retarded in hypothyroid mice or in cultures depleted of T3. In cultured Purkinje cells, PGC-1α knockdown or molecular perturbation of PGC-1α signaling inhibits enhanced dendritic outgrowth and mitochondrial generation and activation caused by T3 treatment. In contrast, PGC-1α overexpression promotes dendrite extension even in the absence of T3. PGC-1α knockdown also downregulates dendrite formation in Purkinje cells . Our findings suggest that the growth-promoting activity of T3 is partly mediated by PGC-1α signaling in developing Purkinje cells.
甲状腺激素3,3',5-三碘-L-甲状腺原氨酸（T3）对正常脑发育至关重要。围产期T3缺失会导致神经元和神经胶质细胞出现严重的生长缺陷，包括小脑皮质浦肯野细胞树突形成受到强烈抑制。在此我们表明，T3通过诱导过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子1α（PGC-1α）来促进浦肯野细胞的树突生长，PGC-1α是线粒体生物发生的主要调节因子。在正常小鼠树突生长过程中，浦肯野细胞中PGC-1α的表达上调，而在甲状腺功能减退的小鼠或缺乏T3的培养物中，其表达则显著延迟。在培养的浦肯野细胞中，PGC-1α基因敲低或PGC-1α信号的分子干扰会抑制T3处理所导致的树突过度生长以及线粒体生成和激活。相反，即使在没有T3的情况下，PGC-1α的过表达也会促进树突延伸。PGC-1α基因敲低还会下调浦肯野细胞中的树突形成。我们的研究结果表明，T3的促生长活性在发育中的浦肯野细胞中部分是由PGC-1α信号介导的。
