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Title: The role of Syk-family protein tyrosine kinases in B cell development
Author: Fallah-Arani, Farnaz
ISNI:       0000 0001 3456 6879
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2006
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The related Syk and Zap70 tyrosine kinases play an important role in lymphocyte development and signalling. Gene targeted mutant mice revealed that Syk plays a significant role in B cell development. Syk'1' mice show a partial block in B cell development at the pro-B to pre-B cell transition and a complete block at the immature to mature B cell transition. In contrast, mice deficient for Zap70 were reported to have normal numbers of B cells, but no T cells due to a block in thymic positive selection. Unexpectedly, mice deficient for both Syk and Zap70 show a complete block in B cell development at the pro-B to pre-B cell transition, indicating that Zap70 plays a role in the B cell lineage as well. I have now further explored the role of Zap70 in B cell development and function. I found that Zap70 is expressed in all developing and mature B cell subsets, although pro-B cells express higher levels of Zap70 than other populations. Analysis of B cell development showed an increase in Bib and marginal zone B cells in Zap70 '1' mice, which was due to the lack of Zap70 in the B cell lineage. In contrast, Zap70-deficient B cells were able to mount normal T-dependent and T-independent immune responses and had unaffected BCR-induced calcium release. Furthermore, I asked whether the distinct effects of Syk and Zap70 mutations on B cell development were due to intrinsic differences in the function of the two kinases, or rather reflected differences in levels of expression. I found that overexpression of Zap70 in Syk'1' mice completely rescued B cell development, arguing that the two kinases are able to perform the same function during B cell development, and that the distinct B cell phenotypes of Syk'1' and Zap 70'1' mice are caused mainly by differences in levels of expression. Finally, to be able to address the role of Syk in mature B cells, I set up a system where I made Syk inducible by fusing the protein to the hormone-binding domain of the estrogen receptor (ER-HBD). Three different Syk-ER fusion constructs were expressed in Syk'1' DT40 cells and one of these was found to restore BCR-induced calcium fluxes in a hormone-dependent manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral