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REGULATION OF GENE ACTIVITY DURING B CELL DEVELOPMENT 
Harinder Singh, Ph.D., Assistant Investigator 
The B cell developmental pathway represents an 
excellent model for understanding the molecular 
basis of differentiation of a defined lineage in mam- 
mals. This pathway is characterized by an ordered 
progression of DNA rearrangements that result in se- 
quential expression of immunoglobulin (Ig) genes. 
B lymphocytes are produced from pluripotent he- 
mopoietic stem cells in the fetal liver and the adult 
bone marrow. Progenitor B (pro-B) cells initiate re- 
arrangement of the Ig heavy-chain locus and de- 
velop into precursor B (pre-B) cells expressing ix 
protein. 
Pre-B cells have been recently shown to express 
four additional lineage-restricted genes (VpreB, X5, 
mb-1, and B29) that encode Ig-associated proteins. 
The VpreB and X5 products represent surrogate 
light-chain proteins that associate with the ix protein 
on the surface of differentiating pre-B cells. The 
mb- 1 and B29 gene products are integral membrane 
proteins that are associated with the ^l receptor on 
pre-B cells and the Ig receptor on B cells. Pre-B 
cells differentiate into mature B cells by productive 
rearrangement and expression of one of two light- 
chain loci, K or X. B cells can then be triggered by 
antigen binding and T cell signals to differentiate 
terminally into Ig-secreting cells. 
Projects in Dr. Singh's laboratory are motivated by 
the assumption that transcriptional control of the 
activities of B-lineage-specific genes represents crit- 
ical regulatory steps in B cell development and 
function. It follows therefore that transcription fac- 
tors implicated in regulating the activities of B- 
lineage-specific genes represent key components 
of the network that orchestrates B cell differentia- 
tion. The experimental "logic" underlying this anal- 
ysis of the molecular control of B cell development 
is as follows: 1) identify a lineage-specific gene that 
is essential for B cell development and/or function, 
2) show that expression of this gene is regulated at 
the level of transcription, 3) identify and character- 
ize cis-acting elements of this gene that regulate its 
transcription, 4 ) identify and characterize transcrip- 
tion factors implicated in regulation of transcrip- 
tional activity, 5) obtain molecular clones of the 
GENETICS 259 
