The generation of mice lacking speci®c components of the transforming growth factor-b (TGF-b) signal tranduction pathway shows that TGF-b is a key player in the development and physiology of the cardiovascular system. Both pro-and anti-angiogenic properties have been ascribed to TGF-b, for which the molecular mechanisms are unclear. Here we report that TGF-b can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-b induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-b/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-b/ ALK1 pathway induces endothelial cell migration and proliferation. We identi®ed genes that are induced speci®cally by TGF-b-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-b/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-b-induced maturation of blood vessels. Our results suggest that TGF-b regulates the activation state of the endothelium via a ®ne balance between ALK5 and ALK1 signalling.

X-linked agammaglobulinaemia (XLA) is a human immunodeficiency caused by failure of pre-B cells in the bone marrow to develop into circulating mature B cells. A novel gene has been isolated which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder. The gene is a member of the src family of proto-oncogenes which encode protein-tyrosine kinases. This is, to our knowledge, the first evidence that mutations in a src-related gene are involved in human genetic disease.

Only mature B lymphocytes can enter the lymphoid follicles of spleen and lymph nodes and thus efficiently participate in the immune response. Mature, long-lived B lymphocytes derive from short-lived precursors generated in the bone marrow. We show that selection into the mature pool is an active process and takes place in the spleen. Two populations of splenic B cells were identified as precursors for mature B cells. Transitional B cells of type 1 (T1) are recent immigrants from the bone marrow. They develop into the transitional B cells of type 2 (T2), which are cycling and found exclusively in the primary follicles of the spleen. Mature B cells can be generated from T1 or T2 B cells.