| Abstract No.: | A-A1005 |
| Country: | Canada |
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| Title: | THE CUB DOMAIN PROTEIN NETO1 MODULATES PLEXIN D1 BINDING SPECIFICITY FOR SECRETED SEMAPHORIN AXON GUIDANCE CUES. |
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| Authors/Affiliations: | 2 Jeffrey R. Gingrich*; 2 David Ng; 1 Bryan Gore; 1 Marc Tessier-Lavigne; 2 Roderick R. McInnes;
1 Department Of Research Drug Discovery, Genentech, Inc., San Francisco, CA,USA; 2 Research Institute, Hospital For Sick Children, Toronto, ON, Canada
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| Content: | The CUB domains of Neto1 are most similar to the CUB domains of neuropilins (Nrps), a family of axon guidance receptor molecules. We found that Neto1 is essential for axon guidance of neurons in several regions of the developing CNS: (i) adult Neto1-null mice display axon projection defects, and (ii) Neto1 is obligatory for midline crossing of commissural interneurons in the embryonic neural tube. Because secreted semaphorins bind to the extracellular CUB domains of the Nrps, we reasoned that a secreted semaphorin may be a ligand for Neto1. We examined the binding of various semaphorins to HEK293 cells co-expressing Nrps or Neto1 and individual plexins. We confirmed that Nrps bind semaphorins even in the absence of a plexin co-receptor. In contrast, Neto1 bound semaphorin 3F (Sema3F) only in the presence of Plexin D1 (PlxnD1), and co-immunoprecipitated with PlxnD1 only in the presence of Sema3F, suggesting that Neto1 and PlxnD1 form a co-receptor for Sema3F. Because PlxnD1 alone binds Sema3E, these findings suggest that Neto1 changes the ligand binding specificity of PlxnD1 from Sema3E to Sema3F. Application of Sema3F to Cos7 cells expressing the Neto1/PlxnD1 co-receptor led to cell retraction, indicating that Sema3F/Neto1/PlxnD1 signalling results in cytoskeletal remodelling consistent with a role in axon guidance. We conclude that Neto1 modulates the specificity of PlxnD1 ligand binding, potentially altering the response of neurons to semaphorin guidance cues during development. |
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