Telling Axons Where To Go ... And Grow

The authors are able to show that the ubiquitin ligase Rnf6polyubiquitinates the kinase LIMK1, targeting it for proteosomaldegradation in the growth cones of hippocampal neurons. LIMK1 regulatesthe dynamics of the actin cytoskeleton primarily via phosphorylation ofthe actin depolymerization factors ADF/cofilin, with importantconsequences for cell morphology, cell motility, and the development ofneuronal projections. Changes in LIMK1 concentration have an impact inneuronal growth cone actin dynamics and axon formation.

The authors focus on the RING finger protein Rnf6 due to itssimilarity to the previously identified protein RLIM, which has beenshown to bind to nuclear LIM domains and critically regulate thebiological activity of LIM-HD transcription factors. The authors findhigh levels of Rnf6 protein in axonal projections of motor neurons anddorsal root ganglia neurons in mouse embryos at a time in whichprojections are actively developing, suggesting a role of this proteinin the development of these neurons. They are able to show that this isindeed the case by RNAi-mediated knock-down of Rnf6 in primaryhippocampal neurons, which stimulate axon outgrowth, and byover-expression of Rnf6 that results in a significant decrease in axonlength.

Finding that Rnf6 targets LIMK1 for degradation finally closesthis circle of regulation, providing the link between actin dynamics,axonal growth and Rnf6. Importantly, the authors are able to show thatchanges in axon outgrowth induced by changes in levels of Rnf6 can berestored by compensatory changes in LIMK1 expression, thereby givingRnf6 a central role in controlling actin dynamics in subcellularstructures. Because LIMK1 has been implicated in biological processessuch as metastasis and invasion of cancer, Dr. Bach points out that"... these results indicate that Rnf6 not only plays an important rolein coordinating neuronal development but may be also involved inoncogenesis."