| First Author | Venigalla RK | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 7 | Pages | 1008-22 |
| PubMed ID | 23463102 | Mgi Jnum | J:195305 |
| Mgi Id | MGI:5477875 | Doi | 10.1038/emboj.2013.40 |
| Citation | Venigalla RK, et al. (2013) PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. EMBO J 32(7):1008-22 |
| abstractText | Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells. |
