Abstract
The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood. In this study, we identify a critical role for the miR-17∼92 microRNA cluster in regulating B-cell central tolerance and demonstrate that these miRNAs control early B-cell development in a cell-intrinsic manner. While the cluster member miR-19 suppresses the expression of Pten and plays a key role in regulating B-cell tolerance, miR-17 controls early B-cell development through other molecular pathways. These findings demonstrate differential control of two closely linked B-cell developmental stages by different members of a single microRNA cluster through distinct molecular pathways.
Highlights
The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood
These miRNAs are highly expressed in progenitor cells, with expression levels decreasing two- to threefold on maturation[13,18]
Mice are engineered to ubiquitously express a superantigen reactive to the heavy chain constant region of IgM, the first B-cell receptor (BCR) expressed on the surface of immature B cells
Summary
The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood. To evaluate the functional contribution of each miRNA subfamily of the miR-17B92 cluster to the regulation of early B cell development, we restored the expression of miR-17B92 miRNAs, either individually or in combination (Fig. 2a), in Mb1tKO HSCs by lentiviral transduction and determined their ability to undergo the pro- to pre-B-cell transition.
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