Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene.
The developmental progression from pro-B to pre-B cells is controlled by pre-B cell receptor (pre-BCR) signaling which depends on BLNK (SLP-65) for coupling the Syk kinase to its downstream effector pathways. Here we identified BLNK as a direct target of the transcription factor Pax5 (BSAP). Restoration of BLNK expression in Ig(mu) transgenic Pax5(-/-) pro-B cells resulted in constitutive pre-BCR signaling and increased cell proliferation without inducing progression to the pre-B cell stage. Ig(mu)(+) Pax5(-/-) pro-B cells expressing a BLNK-estrogen receptor fusion protein initiated signaling immediately upon hormone addition, which facilitated analysis of pre-BCR-induced gene expression changes. The pre-BCR was shown to execute its checkpoint function by regulating genes involved in cell proliferation, intracellular signaling, growth factor responsiveness, and V(D)J recombination.
Schebesta
Michael
M
Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Pfeffer
Peter L
PL
Busslinger
Meinrad
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051757:PAX5 Transcription Factor; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007148:Immunoglobulin mu-Chains; D007527:Isoenzymes; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D010738:Type C Phospholipases; D051966:Phospholipase C gamma