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2. miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

Author

Coffre, Maryaline, Benhamou, David, Rieß, David, Blumenberg, Lili, Snetkova, Valentina, Hines, Marcus J, Chakraborty, Tirtha, Bajwa, Sofia, Jensen, Kari, Chong, Mark MW, Getu, Lelise, Silverman, Gregg J, Blelloch, Robert, Littman, Dan R, Calado, Dinis, Melamed, Doron, Skok, Jane A, Rajewsky, Klaus, and Koralov, Sergei B

Subjects
Spleen, B-Lymphocytes, Animals, Mice, Ribonuclease III, RNA-Binding Proteins, Receptors, Antigen, B-Cell, Proto-Oncogene Proteins c-bcl-2, MicroRNAs, Signal Transduction, Cell Differentiation, Gene Expression Regulation, Down-Regulation, RNA Interference, RNA Editing, Transgenes, Immunoglobulin Light Chains, Proto-Oncogene Proteins c-akt, Forkhead Transcription Factors, Phosphatidylinositol 3-Kinases, B cell development, B lymphocytes, DGCR8, Dicer, Drosha, PI3K/AKT, PTEN, RAG, miRNA, receptor editing, Biochemistry and Cell Biology
Abstract

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.

Published
2016

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