Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system

Netrin 1 is a long-range diffusible factor that exerts chemoattractive or c hemorepulsive effects on developing axons growing to or away from the neura l midline, Here we used tissue explants to study the action of netrin 1 in the migration of several cerebellar and precerebellar cell progenitors. We show that netrin 1 exerts a strong chemoattractive effect on migrating neur ons from the embryonic lower rhombic lip at E12-E14, which give rise to pre cerebellar nuclei. Netrin 1 promotes the exit of postmitotic migrating neur ons from the embryonic lower rhombic lip and upregulates the expression of TAG-1 in these neurons. In addition, in the presence of netrin 1, the migra ting neurons are not isolated but are associated with thick fascicles of ne urites, typical of the neurophilic way of migration. In contrast, the embry onic upper rhombic lip, which contains tangentially migrating granule cell progenitors, did not respond to netrin 1, Finally, in the postnatal cerebel lum, netrin 1 repels both the parallel fibres and migrating granule cells g rowing out from explants taken from the external germinal layer. The develo pmental patterns of expression in vivo of netrin 1 and its receptors are co nsistent with the notion that netrin 1 secreted in the midline acts as chem oattractive cue for precerebellar neurons migrating circumferentially along the extramural stream. Similarly, the pattern of expression in the postnat al cerebellum suggests that netrin 1 could regulate the tangential migratio n of postmitotic premigratory granule cells. Thus, molecular mechanisms con sidered as primarily involved in axonal guidance appear also to steer neuro nal cell migration.