The role of Syk-family protein tyrosine kinases in B cell development.

Fallah-Arani, Farnaz (2006). The role of Syk-family protein tyrosine kinases in B cell development. PhD thesis The Open University.



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.

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