Cell Reports
Volume 17, Issue 9, 22 November 2016, Pages 2271-2285
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Article
miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

https://doi.org/10.1016/j.celrep.2016.11.006Get rights and content
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Highlights

  • Dicer-/Drosha-/DGCR8-dependent ncRNAs are essential for pre-B survival and proliferation

  • Dicer- and DGCR8-dependent miRNAs control the PI3K/AKT/FOXO1 pathway in B cells

  • Regulation of PI3K signaling by miRNAs is essential for keeping Rag expression in check

  • Loss of miRNAs in peripheral B cells leads to immunoglobulin light chain editing

Summary

B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.

Keywords

B lymphocytes
miRNA
Dicer
Drosha
DGCR8
RAG
PTEN
PI3K/AKT
B cell development
receptor editing

Cited by (0)

8

Present address: Hematology and Oncology, Technische Universität München, 81675 Munich, Germany

9

Present address: CRISPR Therapeutics, Cambridge, MA 02139, USA

10

Present address: St. Vincent’s Institute of Medical Research, University of Melbourne, Fitzroy, Australia

11

Present address: Immunity and Cancer Laboratory, The Francis Crick Institute, London NW1 1AT, UK

12

Present address: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany

13

Lead Contact