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The Journal of Neuroscience, March 22, 2006, 26(12):3192-3205; doi:10.1523/JNEUROSCI.3469-05.2006

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Cellular/Molecular
Protein Interacting with C-Kinase 1/Protein Kinase C-Mediated Endocytosis Converts Netrin-1-Mediated Repulsion to Attraction

Joseph L. Bartoe,^1 * William L. McKenna,^1 * Tiffani K. Quan,¹ Benjamin K. Stafford,¹ Jenna A. Moore,¹ Jun Xia,² Kogo Takamiya,² Richard L. Huganir,² and Lindsay Hinck¹

¹Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, and ²Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Lindsay Hinck at the above address. Email: hinck{at}biology.ucsc.edu

In vertebrates, the receptor families deleted in colorectal cancer (DCC) and UNC5 mediate responses to the bifunctional guidance cue netrin-1. DCC mediates attraction, whereas a complex of DCC and UNC5 mediates repulsion. Thus, a primary determinant of the responsiveness of an axon to netrin-1 is the presence or absence of UNC5 family members on the cell surface. Currently, little is known about the role of receptor trafficking in regulating neuronal responses to netrin-1. We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase C (PKC) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKC phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. We find that PKC-stimulated internalization of UNC5A alters the functional response of developing hippocampal axons to netrin-1, preventing UNC5A-mediated growth cone collapse and converting netrin-1-stimulated chemorepulsion to attraction. To address whether this conversion in axonal response occurs in neurons expressing endogenous levels of UNC5, we show that mouse cerebellar granule axons exhibit chemorepulsion in a netrin-1 gradient and that this chemorepulsion is converted to chemoattraction after PKC activation. We demonstrate that this repulsion depends on UNC5A because Unc5a–/– axons are not repelled and show this conversion depends on PICK1 because PICK1–/– axons are not converted to chemoattraction after PKC activation. Together, these data provide a potential mechanism to explain how developing neurons alter their responsiveness to netrin-1 at intermediate choice points as they navigate to their targets.

Key words: trafficking; PICK1; UNC5; netrin-1; axon guidance; PKC

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Received Aug. 16, 2005; revised Feb. 2, 2006; accepted Feb. 3, 2006.

Correspondence should be addressed to Lindsay Hinck at the above address. Email: hinck{at}biology.ucsc.edu

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