The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.
A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro-B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro-B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPalpha and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Ping
P
Lu
Isaiah L
IL
Hankel
Judit
J
Knisz
Andreas
A
Marquardt
Ming-Yi
MY
Chiang
Johannes
J
Grosse
Rainer
R
Constien
Thomas
T
Meyer
Andreas
A
Schroeder
Lutz
L
Zeitlmann
Umaima
U
Al-Alem
Ann D
AD
Friedman
Eric I
EI
Elliott
David K
DK
Meyerholz
Thomas J
TJ
Waldschmidt
Paul B
PB
Rothman
John D
JD
Colgan
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D001483:Base Sequence; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D014176:Protein Biosynthesis; D012326:RNA Splicing / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C582616:Gon4l protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors