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REGULATION OF B CELL DEVELOPMENT BY IMMUNOGLOBULIN M 
Michel C. Nussenzweig, M.D., Ph.D., Assistant Investigator 
Dr. Nussenzweig's research concerns the regula- 
tion of immunoglobulin genes and B lymphocyte 
differentiation. Areas currently under investigation 
include allelic exclusion, and the molecular basis 
for signal transduction by receptor immunoglobu- 
lins. 
Dr. Nussenzweig and his colleagues, in experi- 
ments performed with transgenic mice, have estab- 
lished that allelic exclusion is regulated by the 
membrane-associated form of the immunoglobulin 
heavy chain. In these experiments, rearranged im- 
munoglobulin genes were introduced into the 
germline of mice, and the membrane form of human 
IgM was found to inhibit the expression of endoge- 
nous mouse IgM. In contrast to membrane IgM, the 
secreted form of the same protein had no effect on 
endogenous immunoglobulin genes. These results 
raise two important questions that are currently the 
focus of Dr. Nussenzweig's laboratory: What hap- 
pens at the genetic level that regulates exclusion? 
How does IgM transmit the message that ultimately 
results in exclusion? 
Allelic Exclusion 
There is persuasive evidence that exclusion is reg- 
ulated at the level of immunoglobulin gene rear- 
rangement. Recombination is believed to be initi- 
ated at both sets of parental loci and to be inhibited 
when one of the two alleles achieves a productive 
rearrangement. The finding that membrane immuno- 
globulin is the feedback regulator for allelic exclu- 
sion has been confirmed by several groups. How- 
ever, the mechanism that governs inhibition of 
endogenous immunoglobulin gene expression is 
not well defined. 
One intriguing aspect of exclusion by transgenic 
immunoglobulin is that it is never complete. In 
order to characterize the molecular mechanisms re- 
sponsible for exclusion in transgenic mice and to 
understand the basis for escape from regulation. Dr. 
Nussenzweig and his colleagues have examined the 
rearrangements of endogenous immunoglobulin 
gene segments. The results of these experiments 
suggested that the feedback signal generated by 
membrane-bound IgM produces a gradient along 
the immunoglobulin locus that prevents rearrange- 
ment of 5' gene segments but has little effect on 
the 3' elements. One way to account for these results 
would be to propose that exclusion is regulated 
by both the accessibility of a particular gene seg- 
ment and the availability of the recombination 
machinery. 
To test this two-step model for allelic exclu- 
sion and to explore the role of the recombinase- 
activating genes (RAG) in lymphocyte develop- 
ment. Dr. Nussenzweig and his colleagues have 
created transgenic mice that express the RAG 1 and 
RAG 2 genes in mature T cells. Neither gene alone 
has any effect. However, transgenic mice from six 
independently derived strains that carry both genes 
IMMUNOLOGY 349 
