Abstract
Axon growth is an essential process during brain development. The E3 ubiquitin ligase Cdh1-APC has emerged as a critical regulator of intrinsic axon growth control. Here, we identified the RhoGAP p250GAP as a novel interactor of the E3 ubiquitin ligase Cdh1-APC and found that p250GAP promotes axon growth downstream of Cdh1-APC. We also report that p250GAP undergoes non-proteolytic ubiquitination and associates with the Cdh1 substrate Smurf1 to synergistically regulate axon growth. Finally, we found that in vivo knockdown of p250GAP in the developing cerebellar cortex results in impaired migration and axonal growth. Taken together, our data indicate that Cdh1-APC together with the RhoA regulators p250GAP and Smurf1 controls axon growth in the mammalian brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / metabolism*
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Animals
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Antigens, CD
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Axons / metabolism*
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Cadherins / metabolism*
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Cell Movement
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Cerebellum / cytology
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Cerebellum / growth & development
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Cerebellum / metabolism
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GTPase-Activating Proteins / metabolism*
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HEK293 Cells
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Humans
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Mice
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Rats
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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APC protein, human
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ARHGAP32 protein, human
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Adenomatous Polyposis Coli Protein
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Antigens, CD
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CDH1 protein, human
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Cadherins
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GTPase-Activating Proteins
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rho GTPase-activating protein
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SMURF1 protein, human
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Ubiquitin-Protein Ligases
Grants and funding
This study was supported by the Max Planck Society (J.S.), the German Research Foundation (Deutsche Forschungsgemeinschaft) (J.S.), and the Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences (GGNB) Excellence Stipend of the University of Göttingen (S.J.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.