Richard Sabine, Guyot Romain, Rey-Millet Martin, Prieux Margaux, Markossian Suzy, Aubert Denise, Flamant Frédéric
Univ Lyon, ENS de Lyon, INRAE, CNRS, Institut de Génomique Fonctionnelle de Lyon, 69364 Lyon, France.
Univ Lyon, ENS de Lyon, INRAE, CNRS, Institut de Génomique Fonctionnelle de Lyon, 69364 Lyon, France.
iScience. 2020 Mar 27;23(3):100899. doi: 10.1016/j.isci.2020.100899. Epub 2020 Feb 8.
Mammalian brain development critically depends on proper thyroid hormone signaling, via the TRα1 nuclear receptor. The downstream mechanisms by which TRα1 impacts brain development are currently unknown. In order to investigate these mechanisms, we used mouse genetics to induce the expression of a dominant-negative mutation of TRα1 specifically in GABAergic neurons, the main inhibitory neurons in the brain. This triggered post-natal epileptic seizures and a profound impairment of GABAergic neuron maturation in several brain regions. Analysis of the transcriptome and TRα1 cistrome in the striatum allowed us to identify a small set of genes, the transcription of which is upregulated by TRα1 in GABAergic neurons and which probably plays an important role during post-natal maturation of the brain. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.
哺乳动物的大脑发育严重依赖于通过TRα1核受体进行的适当甲状腺激素信号传导。目前尚不清楚TRα1影响大脑发育的下游机制。为了研究这些机制，我们利用小鼠遗传学方法，在大脑中主要的抑制性神经元——γ-氨基丁酸能（GABAergic）神经元中特异性诱导TRα1显性负性突变的表达。这引发了出生后的癫痫发作，并导致几个脑区的GABA能神经元成熟严重受损。对纹状体中的转录组和TRα1顺反组进行分析，使我们能够鉴定出一小部分基因，这些基因在GABA能神经元中的转录受TRα1上调，并且可能在大脑出生后的成熟过程中发挥重要作用。因此，我们的结果表明，GABA能神经元是大脑发育过程中甲状腺激素的直接靶标，并提示甲状腺功能减退的大脑中出现的许多缺陷可能继发于GABA能神经元功能障碍。
