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PDK1 regulates VDJ recombination, cell‐cycle exit and survival during B‐cell development
Author(s) -
Venigalla Ram K C,
McGuire Victoria A,
Clarke Rosemary,
PattersonKane Janet C,
Najafov Ayaz,
Toth Rachel,
McCarthy Pierre C,
Simeons Frederick,
Stojanovski Laste,
Arthur J Simon C
Publication year - 2013
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2013.40
Subject(s) - biology , b cell , microbiology and biotechnology , recombination activating gene , transcription factor , haematopoiesis , stem cell , gene , genetics , antibody , recombination
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.