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A single microRNA (miRNA) can regulate the expression of many genes, though the level of repression imparted on any given target is generally low. How then is the selective pressure for a single miRNA/target interaction maintained across long evolutionary distances? We addressed this problem by disrupting in vivo the interaction between miR-155 and PU.1 in mice. Remarkably, this interaction proved to be key to promoting optimal T cell-dependent B cell responses, a previously unrecognized role for PU.1. Mechanistically, miR-155 inhibits PU.1 expression, leading to Pax5 down-regulation and the initiation of the plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B-T cell interactions. We conclude that the evolutionary adaptive selection of the miR-155-PU.1 interaction is exercised through the effectiveness of terminal B cell differentiation.

Original publication

DOI

10.1084/jem.20140338

Type

Journal article

Journal

J Exp Med

Publication Date

20/10/2014

Volume

211

Pages

2183 - 2198

Keywords

3' Untranslated Regions, Animals, Antibody Formation, B-Lymphocytes, Base Sequence, Binding Sites, Cell Adhesion, Cell Communication, Cell Differentiation, Gene Expression Regulation, Lymphocyte Activation, Lymphopoiesis, Mice, Mice, Knockout, MicroRNAs, Myelopoiesis, PAX5 Transcription Factor, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins, T-Lymphocytes, Trans-Activators, Transcription Factors