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Rictor Is Required for Early B Cell Development in Bone Marrow

The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTOR...

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Autores principales: Zhang, Yingchi, Hu, Tianyuan, Hua, Chunlan, Gu, Jie, Zhang, Liyan, Hao, Sha, Liang, Haoyue, Wang, Xiaomin, Wang, Weili, Xu, Jing, Liu, Hanzhi, Liu, Bin, Cheng, Tao, Yuan, Weiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119011/
https://www.ncbi.nlm.nih.gov/pubmed/25084011
http://dx.doi.org/10.1371/journal.pone.0103970
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author Zhang, Yingchi
Hu, Tianyuan
Hua, Chunlan
Gu, Jie
Zhang, Liyan
Hao, Sha
Liang, Haoyue
Wang, Xiaomin
Wang, Weili
Xu, Jing
Liu, Hanzhi
Liu, Bin
Cheng, Tao
Yuan, Weiping
author_facet Zhang, Yingchi
Hu, Tianyuan
Hua, Chunlan
Gu, Jie
Zhang, Liyan
Hao, Sha
Liang, Haoyue
Wang, Xiaomin
Wang, Weili
Xu, Jing
Liu, Hanzhi
Liu, Bin
Cheng, Tao
Yuan, Weiping
author_sort Zhang, Yingchi
collection PubMed
description The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1.
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spelling pubmed-41190112014-08-04 Rictor Is Required for Early B Cell Development in Bone Marrow Zhang, Yingchi Hu, Tianyuan Hua, Chunlan Gu, Jie Zhang, Liyan Hao, Sha Liang, Haoyue Wang, Xiaomin Wang, Weili Xu, Jing Liu, Hanzhi Liu, Bin Cheng, Tao Yuan, Weiping PLoS One Research Article The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1. Public Library of Science 2014-08-01 /pmc/articles/PMC4119011/ /pubmed/25084011 http://dx.doi.org/10.1371/journal.pone.0103970 Text en © 2014 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhang, Yingchi
Hu, Tianyuan
Hua, Chunlan
Gu, Jie
Zhang, Liyan
Hao, Sha
Liang, Haoyue
Wang, Xiaomin
Wang, Weili
Xu, Jing
Liu, Hanzhi
Liu, Bin
Cheng, Tao
Yuan, Weiping
Rictor Is Required for Early B Cell Development in Bone Marrow
title Rictor Is Required for Early B Cell Development in Bone Marrow
title_full Rictor Is Required for Early B Cell Development in Bone Marrow
title_fullStr Rictor Is Required for Early B Cell Development in Bone Marrow
title_full_unstemmed Rictor Is Required for Early B Cell Development in Bone Marrow
title_short Rictor Is Required for Early B Cell Development in Bone Marrow
title_sort rictor is required for early b cell development in bone marrow
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119011/
https://www.ncbi.nlm.nih.gov/pubmed/25084011
http://dx.doi.org/10.1371/journal.pone.0103970
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