title: The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons.
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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, and Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA.
authors.forename: Jacqueline H
authors.initials: JH
authors.lastname: Finger
authors.forename: Rod T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Belinda
authors.initials: B
authors.lastname: Harris
authors.forename: Kenneth
authors.initials: K
authors.lastname: Johnson
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Przyborski
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D029742:Caenorhabditis elegans Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D000075389:DCC Receptor; D018628:Gene Dosage; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology; D000075386:Netrin Receptors; D000075388:Netrin-1; D020671:Posterior Horn Cells / Q000473:pathology; D011712:Pyramidal Tracts / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012249:Rhombencephalon / Q000002:abnormalities / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C105653:Unc5c protein, mouse; D000075388:Netrin-1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517679:unc-43 protein, C elegans