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Research Article

Competing molecular interactions of aPKC isoforms regulate neuronal polarity

Sara S. Parker, Edward K. Mandell, Sophie M. Hapak, Irina Y. Maskaykina, Yael Kusne, Ji-Young Kim, Jamie K. Moy, Paul A. St. John, Jean M. Wilson, Katalin M. Gothard, Theodore J. Price, and Sourav Ghosh
  1. Departments of aCellular and Molecular Medicine,
  2. cPharmacology, and
  3. dPhysiology, University of Arizona, Tucson, AZ 85724; and
  4. bNeuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287

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PNAS first published August 12, 2013; https://doi.org/10.1073/pnas.1301588110
Sara S. Parker
Departments of aCellular and Molecular Medicine,
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Edward K. Mandell
Departments of aCellular and Molecular Medicine,
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Sophie M. Hapak
Departments of aCellular and Molecular Medicine,
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Irina Y. Maskaykina
Departments of aCellular and Molecular Medicine,
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Yael Kusne
bNeuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287
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Ji-Young Kim
cPharmacology, and
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Jamie K. Moy
cPharmacology, and
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Paul A. St. John
Departments of aCellular and Molecular Medicine,
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Jean M. Wilson
Departments of aCellular and Molecular Medicine,
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Katalin M. Gothard
dPhysiology, University of Arizona, Tucson, AZ 85724; and
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Theodore J. Price
cPharmacology, and
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  • For correspondence: sourav.ghosh@arizona.edu tjprice@u.arizona.edu
Sourav Ghosh
Departments of aCellular and Molecular Medicine,
bNeuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287
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  • For correspondence: sourav.ghosh@arizona.edu tjprice@u.arizona.edu
  1. Edited by Mu-ming Poo, University of California, Berkeley, CA, and approved July 16, 2013 (received for review January 25, 2013)

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Abstract

Atypical protein kinase C (aPKC) isoforms ζ and λ interact with polarity complex protein Par3 and are evolutionarily conserved regulators of cell polarity. Prkcz encodes aPKC-ζ and PKM-ζ, a truncated, neuron-specific alternative transcript, and Prkcl encodes aPKC-λ. Here we show that, in embryonic hippocampal neurons, two aPKC isoforms, aPKC-λ and PKM-ζ, are expressed. The localization of these isoforms is spatially distinct in a polarized neuron. aPKC-λ, as well as Par3, localizes at the presumptive axon, whereas PKM-ζ and Par3 are distributed at non-axon-forming neurites. PKM-ζ competes with aPKC-λ for binding to Par3 and disrupts the aPKC-λ–Par3 complex. Silencing of PKM-ζ or overexpression of aPKC-λ in hippocampal neurons alters neuronal polarity, resulting in neurons with supernumerary axons. In contrast, the overexpression of PKM-ζ prevents axon specification. Our studies suggest a molecular model wherein mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity.

  • axonogenesis
  • symmetry breaking
  • neurodevelopment

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: sourav.ghosh{at}arizona.edu or tjprice{at}u.arizona.edu.
  • Author contributions: S.S.P., T.J.P., and S.G. designed research; S.S.P., E.K.M., S.M.H., I.Y.M., J.K.M., and K.M.G. performed research; S.S.P., E.K.M., S.M.H., Y.K., J.-Y.K., P.A.S.J., J.M.W., K.M.G., T.J.P., and S.G. analyzed data; and S.S.P., E.K.M., S.M.H., T.J.P., and S.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1301588110/-/DCSupplemental.

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aPKC isoforms in neuronal polarity
Sara S. Parker, Edward K. Mandell, Sophie M. Hapak, Irina Y. Maskaykina, Yael Kusne, Ji-Young Kim, Jamie K. Moy, Paul A. St. John, Jean M. Wilson, Katalin M. Gothard, Theodore J. Price, Sourav Ghosh
Proceedings of the National Academy of Sciences Aug 2013, 201301588; DOI: 10.1073/pnas.1301588110

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aPKC isoforms in neuronal polarity
Sara S. Parker, Edward K. Mandell, Sophie M. Hapak, Irina Y. Maskaykina, Yael Kusne, Ji-Young Kim, Jamie K. Moy, Paul A. St. John, Jean M. Wilson, Katalin M. Gothard, Theodore J. Price, Sourav Ghosh
Proceedings of the National Academy of Sciences Aug 2013, 201301588; DOI: 10.1073/pnas.1301588110
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