Functional role of Netrin in the basal ganglia development

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The mammalian striatum arises in the basal telencephalon and contains morphologically homogenous neurons that can be divided into two distinct compartments, patches and the matrix. During development, patch neurons are generated first to form a striatal primordium. After a large influx of later-born matrix neurons into this region, the unique mosaic arrangement of these two neuronal phenotypes is established. The massive migration of matrix neurons continues during the embryonic period, and they eventually comprise 80-85% of the mature striatum. We found that netrin-1, one of the diffusible guidance cues expressed in the striatal ventricular zone(VZ), exerts a repulsive action on migrating SVZ cells. This effect is blocked in the presence of antibodies against DCC, a putative receptor for netrin-1. The expression patterns of netrin-1 and DCC strongly suggest the involvement of this effect in the outward migration of SVZ cells into the striatal postmitotic region. Our cell tracing study using living brain slices demonstrates that striatal SVZ cells migrate toward and disperse throughout the striatum, in which they differentiate into phenotypes of striatal projection neurons. We suggest that netrin-1 expressed in the striatal VZ serves to guide the large influx of striatal matrix neurons into the striatal primordium and is thereby involved in the initial formation of fundamental striatal structures. We proposed that there are three major modes of neuronal cell migration in the developmental formation of the striatum. They are(radial) outward, tangential, and inward migration, supplying the striatum with projection neurons, interneurons, and early-generated transient neurons that originate in the preplate, respectively.Based on these results, we are currently investigating how Netrin-1 influences migration behaviors of the midbrain dopaminergic neurons employing the Netrin-1 knock-out mice.