Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 14, Pages 5842-5847Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701402104
Keywords
axon growth; dorsal root ganglion neurons; endocytosis; p62
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Funding
- NCRR NIH HHS [P41 RR001192] Funding Source: Medline
- NIDCR NIH HHS [DE016550, R01 DE016550] Funding Source: Medline
- NINDS NIH HHS [NS33661] Funding Source: Medline
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The molecular mechanism and significance of endocytic processes involved in directional axon elongation are not well understood. The Unc-51 family of serine/threonine kinases was shown to be important for axon growth and was also linked to endocytosis, providing an entry point to study this problem. We found that mouse Unc-51-like kinase 1/2 (Ulk1/2) proteins are localized to vesicular structures in growth cones of mouse spinal sensory neurons. RNAi-mediated knockdown of Ulk1 and/or Ulk2 resulted in impaired endocytosis of nerve growth factor (NGF), excessive axon arborization, and severely stunted axon elongation. The evidence also indicates that Ulk1/2 mediates a non-clathrin-coated endocytosis in sensory growth cones. Interestingly, NGF can induce the interaction of Ulk1 with TrkA receptor complexes through promoting K63-polyubiquitination of Ulk1 and binding of Ulk1 to the scaffolding protein p62. These results and additional studies suggest that Ulk1/2 proteins regulate filopodia extension and neurite branching during sensory axon outgrowth, probably through regulating TrkA receptor trafficking and signaling.
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