Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice.
Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice.
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条件性敲除 RORγt 表达细胞中的 Tsc1 会导致小鼠脑损伤和早期死亡
DOI：
10.1186/s12974-021-02153-8
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发表时间：
2021-05-06
影响因子：
9.3
通讯作者：
Deng Y
中科院分区：
文献类型：
--
作者：
Deng Y;Yang Q;Yang Y;Li Y;Peng H;Wu S;Zhang S;Yao B;Li S;Gao Y;Li X;Li L;Deng Y
已知脑硬化症复合物1（Tsc 1）调节各种细胞类型的发育和功能，并且RORγt是免疫系统中的关键转录因子。然而，Tsc 1是否参与调节RORγ t表达细胞仍不清楚。我们建立了一个小鼠模型，其中Tsc 1从RORγ t表达细胞中条件性缺失（Tsc 1 ROR γt），以研究Tsc 1缺陷的RORγ t表达细胞在脑内稳态中的作用。Tsc 1 ROR γt小鼠的3型先天淋巴细胞（ILC 3）显示正常的发育和功能，并且小鼠显示正常的Th 17细胞分化。然而，Tsc 1 ROR γt小鼠表现出自发性强直-阵挛性癫痫发作，并在出生后4 - 6周死亡。在4周龄时，在表达RORγ t的细胞中特异性敲除Tsc 1的小鼠出现皮质神经元缺陷和海马结构异常。值得注意的是，在Tsc 1 ROR γt小鼠的皮质和海马中观察到神经元的过度活化和星形胶质细胞增生。此外，Tsc 1 ROR γt小鼠脑内γ-氨基丁酸（GABA）受体的表达降低，补充GABA在一定程度上延长了小鼠的寿命。进一步的实验揭示了小鼠脑中存在一组具有高代谢活性的罕见RORγ t表达细胞。我们的研究证实了以前未被注意到的RORγ t表达细胞在大脑中的关键作用，并证明了RORγ t表达细胞中的Tsc 1信号通路对维持大脑稳态很重要。在线版本包含补充材料，可通过10.1186/s12974-021-02153-8获得。
Tuberous sclerosis complex 1 (Tsc1) is known to regulate the development and function of various cell types, and RORγt is a critical transcription factor in the immune system. However, whether Tsc1 participates in regulating RORγt-expressing cells remains unknown. We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1RORγt) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis. Type 3 innate lymphoid cells (ILC3s) in Tsc1RORγt mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1RORγt mice exhibited spontaneous tonic-clonic seizures and died between 4 and 6 weeks after birth. At the age of 4 weeks, mice in which Tsc1 was specifically knocked out in RORγt-expressing cells had cortical neuron defects and hippocampal structural abnormalities. Notably, over-activation of neurons and astrogliosis were observed in the cortex and hippocampus of Tsc1RORγt mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1RORγt mice was decreased, and GABA supplementation prolonged the lifespan of the mice to some extent. Further experiments revealed the presence of a group of rare RORγt-expressing cells with high metabolic activity in the mouse brain. Our study verifies the critical role of previously unnoticed RORγt-expressing cells in the brain and demonstrates that the Tsc1 signaling pathway in RORγt-expressing cells is important for maintaining brain homeostasis. The online version contains supplementary material available at 10.1186/s12974-021-02153-8.
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