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

BACKGROUND: 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. METHODS: We generated a...

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Autores principales: Deng, Yafei, Yang, Qinglan, Yang, Yao, Li, Yana, Peng, Hongyan, Wu, Shuting, Zhang, Shuju, Yao, Baige, Li, Shuhui, Gao, Yuan, Li, Xiaohui, Li, Liping, Deng, Youcai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101034/
https://www.ncbi.nlm.nih.gov/pubmed/33957945
http://dx.doi.org/10.1186/s12974-021-02153-8
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author Deng, Yafei
Yang, Qinglan
Yang, Yao
Li, Yana
Peng, Hongyan
Wu, Shuting
Zhang, Shuju
Yao, Baige
Li, Shuhui
Gao, Yuan
Li, Xiaohui
Li, Liping
Deng, Youcai
author_facet Deng, Yafei
Yang, Qinglan
Yang, Yao
Li, Yana
Peng, Hongyan
Wu, Shuting
Zhang, Shuju
Yao, Baige
Li, Shuhui
Gao, Yuan
Li, Xiaohui
Li, Liping
Deng, Youcai
author_sort Deng, Yafei
collection PubMed
description BACKGROUND: 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. METHODS: We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1(RORγt)) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis. RESULTS: Type 3 innate lymphoid cells (ILC3s) in Tsc1(RORγt) mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1(RORγt) 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 Tsc1(RORγt) mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1(RORγt) 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02153-8.
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spelling pubmed-81010342021-05-06 Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice Deng, Yafei Yang, Qinglan Yang, Yao Li, Yana Peng, Hongyan Wu, Shuting Zhang, Shuju Yao, Baige Li, Shuhui Gao, Yuan Li, Xiaohui Li, Liping Deng, Youcai J Neuroinflammation Research BACKGROUND: 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. METHODS: We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1(RORγt)) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis. RESULTS: Type 3 innate lymphoid cells (ILC3s) in Tsc1(RORγt) mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1(RORγt) 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 Tsc1(RORγt) mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1(RORγt) 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02153-8. BioMed Central 2021-05-06 /pmc/articles/PMC8101034/ /pubmed/33957945 http://dx.doi.org/10.1186/s12974-021-02153-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Deng, Yafei
Yang, Qinglan
Yang, Yao
Li, Yana
Peng, Hongyan
Wu, Shuting
Zhang, Shuju
Yao, Baige
Li, Shuhui
Gao, Yuan
Li, Xiaohui
Li, Liping
Deng, Youcai
Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title_full Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title_fullStr Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title_full_unstemmed Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title_short Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice
title_sort conditional knockout of tsc1 in rorγt-expressing cells induces brain damage and early death in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101034/
https://www.ncbi.nlm.nih.gov/pubmed/33957945
http://dx.doi.org/10.1186/s12974-021-02153-8
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