In a recent study, Dr. Ingolf Bach and colleagues from the University of Massachusetts Medical School, Worcester and the University of Hamburg describe a novel role for the ubiquitin/proteosome protein degradation pathway in the regulation of local actin dynamics in neurons.
The authors are able to show that the ubiquitin ligase Rnf6 polyubiquitinates the kinase LIMK1, targeting it for proteosomal degradation in the growth cones of hippocampal neurons. LIMK1 regulates the dynamics of the actin cytoskeleton primarily via phosphorylation of the actin depolymerization factors ADF/cofilin, with important consequences for cell morphology, cell motility, and the development of neuronal projections. Changes in LIMK1 concentration have an impact in neuronal growth cone actin dynamics and axon formation.
The authors focus on the RING finger protein Rnf6 due to its similarity to the previously identified protein RLIM, which has been shown to bind to nuclear LIM domains and critically regulate the biological activity of LIM-HD transcription factors. The authors find high levels of Rnf6 protein in axonal projections of motor neurons and dorsal root ganglia neurons in mouse embryos at a time in which projections are actively developing, suggesting a role of this protein in the development of these neurons. They are able to show that this is indeed the case by RNAi-mediated knock-down of Rnf6 in primary hippocampal neurons, which stimulate axon outgrowth, and by over-expression of Rnf6 that results in a significant decrease in axon length.
Finding that Rnf6 targets LIMK1 for degradation finally closes this circle of regulation, providing the link between actin dynamics, axonal growth and Rnf6. Importantly, the authors are able to show that changes in axon outgrowth induced by changes in levels of Rnf6 can be restored by compensatory changes in LIMK1 expression, thereby giving Rnf6 a central role in controlling actin dynamics in subcellular structures. Because LIMK1 has been implicated in biological processes such as metastasis and invasion of cancer, Dr. Bach points out that "…these results indicate that Rnf6 not only plays an important role in coordinating neuronal development but may be also involved in oncogenesis."