Developmental Genetics 
these are authentic homologous recombination 
events. 
ES cells have been used to generate germline 
chimeras. Animals heterozygous for the src muta- 
tion exhibit no phenotype, whereas homozygous 
animals survive to birth but are retarded relative 
to their littermates and die in the first few weeks. 
Further analysis of these animals reveals an osteo- 
clast defect and resulting osteopetrosis. This re- 
sult is surprising, for it implies that src may not 
be essential for cell types in which it is most 
highly expressed. 
In many cell types, other tyrosine kinases re- 
lated to c-src may play overlapping roles. We are 
particularly interested in the c-yes and fyn genes. 
To study these, we have generated mutations in 
ES cells by homologous recombination in c-yes 
and are designing similar experiments with fyn. 
The frequency of homologous recombination at 
the c-yes locus has been about 1 in 30, and the 
yes chimeras will be bred to ascertain contribu- 
tion to the germline. The resulting mutant mice 
may be examined for the effect of loss of yes and 
crossed to src-deficient mice to examine the in- 
terplay between different members of the src 
gene family. 
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