Abstract
PP4 phosphatase regulates a number of crucial processes but the role of PP4 in B cells has never been reported. We generated B cell-specific pp4 knockout mice and have identified an essential role for PP4 in B cell development. Deficiency of PP4 in B lineage cells leads to a strong reduction in pre-B cell numbers, an absence in immature B cells, and a complete loss of mature B cells. In PP4-deficient pro-B cells, immunoglobulin (Ig) DJH recombination is impaired and Ig µ heavy chain expression is greatly decreased. In addition, PP4-deficient pro-B cells show an increase of DNA double-strand breaks at Ig loci. Consistent with their reduced numbers, residual PP4-deficient pre-B cells accumulate in the G1 phase, exhibit excessive DNA damage, and undergo increased apoptosis. Overexpression of transgenic Ig in PP4-deficient mice rescues the defect in B cell development such that the animals have normal numbers of IgM+ B cells. Our study therefore reveals a novel function for PP4 in pro-B cell development through its promotion of VHDJH recombination.
Highlights
B cell development initiates in the bone marrow (BM) of adult mice and is a tightly controlled process
We describe the essential role of phosphatase 4 (PP4) in early B cell development through its regulation of Ig DJH/VHDJH recombination
Utilizing the mb-1/cre-flox system to generate cKO mice, we have shown that cre activity under the control of the mb-1 promoter initiates at the pre-pro-B cell stage
Summary
B cell development initiates in the bone marrow (BM) of adult mice and is a tightly controlled process. The process starts with D-JH recombination in Fr. A cells, followed by VH-DJH recombination in Fr. B and Fr. C cells [2], [3]. Successful Ig VHDJH/VLJL recombination leads to the expression of a surface IgM-containing BCR complex that enables a B cell to continue to the Fr. E and Fr. F stages [4]. DJH/VHDJH recombination is initiated when two Ig gene segments flanked by recombination signal sequences (RSSs) are paired and cleaved by RAG [5], [6]. A deficiency of any of these factors results in a failure in DJH/VHDJH recombination, an early block in B cell development, and a shortage of mature B lymphocytes [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
