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MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation

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Abstract

Axons of the corpus callosum (CC), the white matter tract that connects the left and right hemispheres of the brain, receive instruction from a number of chemoattractant and chemorepulsant cues during their initial navigation towards and across the midline. While it has long been known that the CC is malformed in the absence of Myristoylated alanine-rich C-kinase substrate (MARCKS), evidence for a direct role of MARCKS in axon navigation has been lacking. Here, we show that MARCKS is necessary for Netrin-1 (NTN1) signaling through the DCC receptor, which is critical for axon guidance decisions. Marcks null (Marcks−/−) neurons fail to respond to exogenous NTN1 and are deficient in markers of DCC activation. Without MARCKS, the subcellular distributions of two critical mediators of NTN1-DCC signaling, the tyrosine kinases PTK2 and SRC, are disrupted. Together, this work establishes a novel role for MARCKS in axon dynamics and highlights the necessity of MARCKS as an organizer of DCC signaling at the membrane.

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Acknowledgements

This work was supported by a Department of Defense National Defense Science & Engineering Graduate (NDSEG) fellowship for J.J.B., a University of South Dakota Center for Brain and Behavior Research (CBBRe) trainee research grant for J.J.B., the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (D.J.S. and P.J.B.), and a grant from the National Institutes of Health to J.M.W. (R01NS082283). This work also received support from the Sanford Research Imaging Core and the Sanford Research Protein Biochemistry Core, both within the Sanford Research Center for Pediatric Research (National Institutes of Health P20GM103620).

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Authors and Affiliations

  1. Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA

    J. J. Brudvig, J. T. Cain, G. G. Schmidt-Grimminger & J. M. Weimer

  2. Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, 57069, USA

    J. J. Brudvig

  3. Signal Transduction Laboratory, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA

    D. J. Stumpo & P. J. Blackshear

  4. Enabling Technologies Group, Sanford Research, Sioux Falls, SD, 57104, USA

    K. J. Roux

  5. Department of Pediatrics, University of South Dakota, Sioux Falls, SD, 57105, USA

    K. J. Roux & J. M. Weimer

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  1. J. J. Brudvig
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Correspondence to J. M. Weimer.

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Animal protocols were approved by the Sanford Research Institutional Animal Care and Use Committee (USDA License 46-R-0009) with all procedures carried out in strict accordance with National Institutes of Health guidelines and the Sanford Research Institutional Animal Care and Use Committee guidelines.

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Brudvig, J.J., Cain, J.T., Schmidt-Grimminger, G.G. et al. MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation. Mol Neurobiol 55, 8388–8402 (2018). https://doi.org/10.1007/s12035-018-0990-3

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