Editors' ChoiceNeuroscience

How Smurfs Control Axon Formation

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Science's STKE  13 Mar 2007:
Vol. 2007, Issue 377, pp. tw83
DOI: 10.1126/stke.3772007tw83

In the course of development, hippocampal neurons normally produce multiple equivalent neurites, only one of which eventually becomes the axon of a polarized neuron. The small guanosine triphosphatase (GTPase) Rap1B is a necessary and sufficient regulator of this process and is initially present in each of the neurites, but is later present only in the neurite destined to become the axon. Results from Schwamborn et al. show that this critical loss of Rap1B is mediated by ubiquitin-dependent degradation of the GTPase. Treatment of cultured hippocampal neurons from rat embryos with various inhibitors of the proteasome caused formation of extra axons. In transfected cells or in vitro binding assays, a catalytically inactive mutant of the ubiquitin ligase Smurf2 could be immunoprecipitated with a dominant-negative mutant of Rap1 and associated with nucleotide-free or GDP-bound Rap1, but not with Rap1 bound to a nonhydrolyzable analog of GTP. These results indicate that the ligase recognizes only inactive Rap1. Depletion of Smurf2 also caused formation of supernumerary axons in the cultured neurons. Thus, the authors propose that the ubiquitination and proteasome-dependent degradation of Rap1B is required for selection of a single neurite that becomes the axon. In their model, through a mechanism not yet revealed, one of the neurites would have higher activity of Rap1. Because the active GTPase is resistant to degradation, the Smurf-induced degradation would occur primarily in the remaining neurites with low Rap1B activity, thus converting the quantitative differences in Rap1B activity to a switchlike mechanism that allows only a single neurite to go on to form the axon.

J. C. Schwamborn, M. Müller, A. H. M. Becker, A. W. Püschel, Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. EMBO J. 26, 1410-1422 (2007). [Online Journal]

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