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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.



Autor: Yingchi Zhang , Tianyuan Hu , Chunlan Hua , Jie Gu, Liyan Zhang, Sha Hao, Haoyue Liang, Xiaomin Wang, Weili Wang, Jing Xu, Hanzhi

Fuente: http://plos.srce.hr/



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