Abstract
Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target. Netrin 1, a bifunctional cue involved in both attracting and repelling axons, is involved in many cell migration and axon pathfinding processes in the CNS. The netrin 1 receptor DCC and its Caenorhabditis elegans homolog UNC-40 have been implicated in directing the guidance of axons toward netrin sources, whereas the C. elegans UNC-6 receptor, UNC-5 is necessary for migrations away from UNC-6. However, a role of vertebrate UNC-5 homologs in axonal migration has not been demonstrated. We demonstrate that the Unc5h3 gene product, shown previously to regulate cerebellar granule cell migrations, also controls the guidance of the corticospinal tract, the major tract responsible for coordination of limb movements. Furthermore, we show that corticospinal tract fibers respond differently to loss of UNC5H3. In addition, we observe corticospinal tract defects in mice homozygous for a spontaneous mutation that truncates the Dcc transcript. Postnatal day 0 netrin 1 mutant mice also demonstrate corticospinal tract abnormalities. Last, interactions between the Dcc and Unc5h3 mutations were observed in gene dosage experiments. This is the first evidence of an involvement in axon guidance for any member of the vertebrate unc-5 family and confirms that both the cellular and axonal guidance functions of C. elegans unc-5 have been conserved in vertebrates.
Highlights
Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target
The dorsal funiculus is composed of three axonal tracts: the ascending gracilis and cuneatus tracts, which enter the spinal cord from the hindlimbs and forelimbs, respectively, and the descending corticospinal tract, which resides in the ventralmost portion of the dorsal funiculus (Joosten, 1990; Stanfield, 1992)
Our results demonstrate that netrin 1 and two of its receptors, UNC5H3 and DCC, are necessary at multiple points along the migration of the longest mammalian axonal tract, the corticospinal tract (Fig. 12)
Summary
Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target. The Caenorhabditis elegans bifunctional cue UNC-6 guides axon migrations by attractive or repulsive mechanisms depending on the response of its receptor (Hedgecock et al, 1990; Wadsworth et al, 1996; Culotti and Merz, 1998). Additional cues are necessary for axons to cross the midline, such as axonin-1 (contactin 2) and NrCAM (Stoeckli and Landmesser, 1998) Another receptor molecule, Roundabout (Robo), is postulated to be required on the axons to prevent them from recrossing the midline, presumably by repulsion from Slit expressed at the midline (Li et al, 1999). The migration route of axons appears broken down into steps, each of which requires a particular set of molecules
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