In more recent experiments it has been possible 
to use homologous recombination in embryonic 
stem cells to produce mice bearing a homozygous 
disruption of the fyn locus. Detailed analysis of 
these animals promises to permit a more complete 
dissection of the biochemical wiring that links lym- 
phocyte surface proteins to regulators of gene ex- 
pression. 
The Ick Promoter System 
Because p56''^* participates in the control of nor- 
mal thymocyte development, it is perhaps not sur- 
prising that the expression of the Ick gene is itself 
tightly regulated. Members of Dr. Perlmutter's labo- 
ratory have characterized the structures of the mu- 
rine and human Ick genes and have defined two 
promoters in each gene that function in a develop- 
mentally restricted fashion. The 3' (or proximal) Ick 
promoter is active only in immature thymocytes, 
while the 5' (or distal) promoter functions mainly in 
mature T cells. Through a series of gene deletion 
and mapping experiments, minimal sequences capa- 
ble of directing tissue-specific and temporally 
correct expression of heterologous DNA elements 
have been defined for both promoters. 
In this way, an extremely useful set of reagents has 
been developed for use in the generation of trans- 
genic mice. Indeed, more than 30 different genes 
have been expressed in a thymus-specific fashion in 
transgenic mice using the proximal Ick promoter. It 
now appears that expression of Ick transcripts marks 
an important early step in T cell lineage commit- 
ment. A thorough dissection of the nuclear factors 
that regulate Ick gene expression promises to illumi- 
nate mechanisms controlling thymopoiesis. 
Dr. Perlmutter is also Professor of Immunol- 
ogy, Medicine, and Biochemistry at the University 
of Washington School of Medicine, Seattle. 
Books and Chapters of Books 
Abraham, K.M., Levin, S.D., Cooke, M.P., and Perl- 
mutter, R.M. 1991. Transgenic systems for the 
analysis of src- family kinase function. In Ad- 
vances in Regulation of Cell Growth: Genetic 
Approaches to Understanding Cell Activation. 
New York: Raven, vol 2, pp 231-250. 
Articles 
Allen, J.M., Forbush, K.A., and Perlmutter, R.M. 
1992. Functional dissection of the Ick proximal 
promoter. Mot Cell Biol 12:2758-2768. 
Chaffin, K.E., and Perlmutter, R.M. 1991. A per- 
tussis toxin-sensitive process controls thymocyte 
emigration. Eur J Immunol 21:2565-2573- 
Ingraham, C.A., Cooke, M.P., Chuang, Y.N., Perl- 
mutter, R.M., and Maness, P.F. 1992. Cell type 
and developmental regulation of the fyn proto- 
oncogene in neural retina. Oncogene 7:95-100. 
Perlmutter, R.M. 1991 . Translational regulation of 
the lymphocyte-specific protein tyrosine kinase 
p56'''*. Enzyme 44:214-224. 
van Oers, N.S.C., Garvin, A.M., Davis, C.B., For- 
bush, K.A., Carlow, D.A., Littman, D.R., Perl- 
mutter, R.M., and Teh, H.-S. 1992. Disruption of 
CD8-dependent negative and positive selection of 
thymocytes is correlated with a decreased associa- 
tion between CDS and the protein tyrosine ki- 
nase, p56'''*. Eur f Immunol 22:735-743. 
REGULATION OF EXPRESSION OF CLASS II MHC AND HIV GENES 
B. Matija Peterlin, M.D., Associate Investigator 
Dr. Peterlin and his co-workers are studying the 
regulation of expression of class II major histocom- 
patibility complex (MHC; class II, DR) and human 
immunodeficiency virus (HIV) proteins. In hu- 
mans, different levels of expression of these pro- 
teins lead to severe combined immunodeficiency 
and/or autoimmunity. Class II and HIV are further 
linked by genetics, since low expression of each can 
be complemented in trans, i.e., by rescuing the 
gene(s) missing or mutated in the class II bare lym- 
phocyte syndrome (BLS II; one of only two known 
hereditary deficiencies in a regulatory protein in 
humans) and by HIV-encoded trans-activators Tat 
and Rev. 
Regulation of Class II Gene Expression 
Class II antigens are peptide carriers that present 
self and foreign peptides on antigen-presenting cells 
to T cells to initiate, and to B cells to propagate, the 
immune response. Developmentally, class II anti- 
gens must be expressed in the thymus to tolerize T 
cells to self peptides and to restrict T cells to non- 
self peptides. For these interactions to occur, the 
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