Migrating neurons in the cerebral cortex

Victor Tybulewicz group project:

Rac1 and Rac2

Rac1 and Rac2 are small GTPases of the Rho-family, which have been implicated in the control of the actin cytoskeleton, signal transduction, cell proliferation, and apoptosis (Tybulewicz and Henderson, 2009). Since the knockout of Rac1 is an early embryonic lethal, we have generated a conditional allele of Rac1, flanked by loxP sites which allows deletion of the gene by the Cre recombinase. Using this we have been able to inactivate Rac1 in a tissue-specific manner, and have shown that deletion of Rac1 and Rac2 results in a severe block in late B cell development, at the transitional B cell stage in the spleen (Walmsley et al, 2003).  We have gone on to show that this is due to an inability of the transitional cells to migrate into the white pulp of the spleen and proposed that this migration is a key developmental checkpoint during B cell positive selection (Henderson et al, 2010).

Deletion of Rac1 and Rac2 during early T cell development, leads to a strong developmental block in the thymus caused by defective pre-TCR signaling (Dumont et al, 2009). In contrast, deletion of both GTPases in mature T cells results in defective migration of T cells into and through lymph nodes (Faroudi et al, 2010). The GTPases are important for homing to the lymph node, adhesion to the high endothelial venules, transmigration across them, interstitial migration within the lymph node parenchyma and egress from the lymph node.

Rac GTPases control entry into splenic white pulp

Rac GTPases control entry into splenic white pulp

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Rac2-deficient B cells (green) are excluded from the white pulp of the spleen, whose edges are identified by expression of MadCAM-1 (red).

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