Rictor is required for early B cell development in bone marrow

PLoS One. 2014 Aug 1;9(8):e103970. doi: 10.1371/journal.pone.0103970. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism*
  • Blood Cells / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Cycle / drug effects
  • Cell Differentiation* / drug effects
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Deletion
  • Gene Knockdown Techniques
  • Homeodomain Proteins / metabolism
  • Mice, Inbred C57BL
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Sirolimus / pharmacology
  • Spleen / metabolism

Substances

  • Carrier Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Homeodomain Proteins
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • RAG-1 protein
  • Sirolimus

Grants and funding

Funds from the Ministry of Science and Technology of China (2012CB966604, 2013CB966902, 2011CB964801, 2013BAI01B09) supported this study in study design and data collection. WPY and TC received these funds. Funds from National Natural Science Foundation (81090410, 81130074, 81330015, 81070390, 81300374, 81300436) supported this study in analysis, decision to publish and preparation of this manuscript. WPY and TC received these funds.