Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice

Journal of Neuroinflammation

Shuhui Li¹  Baige Yao²  Shuting Wu³  Hongyan Peng³  Yafei Deng³  Liping Li³  Shuju Zhang³  Qinglan Yang³  Yana Li³  Xiaohui Li⁴  Youcai Deng⁴  Yao Yang⁴  Yuan Gao⁵ 

[1] Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University (Third Military Medical University), 400038, Chongqing, China;Department of Pharmacy, The Third Xiangya Hospital, Central South University, 410000, Changsha, China;Hunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, 410000, Changsha, China;Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), 400038, Chongqing, China;Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, 400038, Chongqing, China;

关键词: RORγt-;    Tsc1;    GABA;    Seizure;   

DOI  :  10.1186/s12974-021-02153-8

来源: Springer

【 摘 要 】

BackgroundTuberous 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.MethodsWe 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.ResultsType 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.ConclusionsOur 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.

【 授权许可】

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