PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development

Ram K C Venigalla (Lead / Corresponding author), Victoria A McGuire, Rosemary Clarke, Janet C Patterson-Kane, Ayaz Najafov, Rachel Toth, Pierre C McCarthy, Frederick Simeons, Laste Stojanovski, J Simon C. Arthur (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)1008-22
    Number of pages15
    JournalEMBO Journal
    Volume32
    Issue number7
    DOIs
    Publication statusPublished - 3 Apr 2013

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