Ooi, Steen Kian Thye; (2003) The role of Rac GTPases in B cell development and activation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

B cell antigen receptor (BCR)-derived signals are crucial for the normal development, and activation of B cells. Rac-family small GTPases are involved in transducing BCR- derived signals. Members of this family are highly homologous, suggesting that they may have overlapping, redundant functions. Analysis of mice deficient for the haematopoietic- specific Rac2 has illustrated its importance in normal B cell development and function. The role of Racl has not yet been addressed as genetic deficiency for this results in embryonic lethality. In order to address both the role of Racl in B cell biology and potential functional redundancy between Racl and Rac2, I analysed B cell development and activation using conventional and conditional mutagenesis approaches. Analysis of B cell development in Rac2-/- mice revealed perturbations in the B-la, marginal zone and mature B cell compartments, which is in agreement with published data. Analysis of Rac1+/- Rac2-/- mice revealed these defects were further exacerbated, demonstrating that in the absence of Rac2, Rac1 can compensate for Rac2. A conditional mutagenesis approach was used to generate mice with deletion of the Rac1 gene in B lineage cells only (Rac1B mice). These mice possess no defect in B cell development. To generate B cells deficient for both Rac1 and Rac2, Rac1BRac2-/- mice were generated by breeding. Analysis of B cell development revealed a complete absence of mature B cells deficient for both Rac1 and Rac2, illustrating that both are necessary for normal mature B cell development. Rac2 was found to be important in transducing BCR-mediated responses in mature B cells resulting in calcium mobilisation, survival, cell cycle entry and the expression of the activation marker CD69. Analysis of Rac1+/-Rac2-/- B cells revealed that Rac1 is also involved in these processes, although Rac1 plays little if any role in BCR-induced calcium mobilisation. Finally, I also showed that Rac1 and Rac2 are involved in transducing BCR-derived signals necessary for up-regulating receptor(s) for the survival molecule BAFF.

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