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The Journal of Neuroscience, August 29, 2007, 27(35):9458-9468; doi:10.1523/JNEUROSCI.0870-07.2007

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Cellular/Molecular
Protein Kinase C{zeta} and Glycogen Synthase Kinase-3ß Control Neuronal Polarity in Developing Rodent Enteric Neurons, whereas SMAD Specific E3 Ubiquitin Protein Ligase 1 Promotes Neurite Growth But Does Not Influence Polarity

Bhupinder P. S. Vohra, Ming Fu, and Robert O. Heuckeroth

Departments of Pediatrics, and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Dr. Robert O. Heuckeroth, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, MO 63110. Email: heuckeroth{at}kids.wustl.edu

Enteric nervous system (ENS) precursors migrate extensively before differentiating to form uni-axonal or multi-axonal neurons. ENS precursor survival, neurite growth, and cell migration are all directed by Ret kinase, but downstream signaling pathways are incompletely understood. We now demonstrate that proteins regulating polarity in other cells including partitioning defective 3 (PAR3), PAR6, protein kinase C{zeta} (PKC{zeta}), and glycogen synthase kinase 3ß (GSK3ß) are expressed in developing enteric neurons with a polarized distribution. Blocking PKC{zeta} or GSK3ß reduces ENS precursor migration and induces the formation of multi-axonal neurons. Axon elongation also depends on SMURF1 (SMAD specific E3 ubiquitin protein ligase 1), which promotes RhoA degradation and associates with polarity proteins. SMURF1 inhibition, however, does not increase the number of multi-axonal neurons in ENS precursors. These data link cell surface Ret activation with molecular machinery controlling cytoskeletal dynamics and suggest that polymorphisms influencing PKC{zeta} or GSK3ß might alter Hirschsprung disease penetrance or expressivity by affecting ENS precursor migration.

Key words: neuronal polarity; migration; axon specification; partitioning proteins; intracellular signaling; neurite

Received Feb. 26, 2007; revised June 7, 2007; accepted July 6, 2007.

Correspondence should be addressed to Dr. Robert O. Heuckeroth, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, MO 63110. Email: heuckeroth{at}kids.wustl.edu






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