EXPRESSION OF TIAM-1 IN THE DEVELOPING BRAIN SUGGESTS A ROLE FOR THE TIAM-1-RAC SIGNALING PATHWAY IN CELL-MIGRATION AND NEURITE OUTGROWTH

During development proper neuronal migration and neurite extension are essential for the formation of functional neuronal networks. These pr ocesses require the reorganization of the cytoskeleton by modifying th e dynamics of actin filaments and microtubules. The Rho subfamily of G TPases regulates actin cytoskeletal changes during development. Tiam-1 , a GDP-GTP exchange factor for the small GTPase Rac and implicated in tumor invasion and metastasis, is expressed in the developing CNS. To study the function of Tiam-1 in neuronal migration and neurite extens ion, we examined the pattern of Tiam-1 expression in weaver mice, in w hich cerebellar granule cells fail to migrate to their final position and subsequently die. Tiam-1 is expressed in wild-type granule cells a s they migrate to the internal granular layer and send axons. In contr ast, weaver homozygous animals do not express Tiam-1 in premigratory g ranule cells. Heterozygous animals, in which granule cells exhibit a s low rate of migration, express low levels of Tiam-1. In the cerebral c ortex, Tiam-1 is also expressed in migrating neurons. Our findings sug gest that Tiam-1 contributes to cytoskeletal reorganization required d uring cell migration and neurite extension in defined neuronal populat ions, presumably by activation of Rac.