Early in development, neurons form neurites; one neurite elongates to become an axon and the others then become dendrites (see Pinheiro and Gertler). But what "primes" that neurite to become the axon? Localized activation of the small guanosine triphosphatase (GTPase) Rac, which regulates the actin cytoskeleton and microtubule dynamics, has been implicated in axon formation, leading Watabe-Uchida et al. to search for upstream regulators involved in establishing neuronal polarity. A yeast two-hybrid screen of a human fetal cDNA brain library with a dominant-negative Rac1 mutant identified DOCK7 (dedicator of cytokinesis 7), one of a family of unconventional Rho family guaninenucleotide exchange factors, as a binding partner. DOCK7 was highly expressed in rat brain and was most abundant during late embryonic and early postnatal development. In primary cultures of hippocampal neurons, DOCK7 was most abundant at the time axons appeared and was preferentially expressed in one of the early neurites and then in the developing axon. DOCK7 overexpression did not affect the total number of neurites but increased the number of axons; a mutant form of DOCK7 that did not activate Rac failed to induce additional axons (and sometimes prevented formation of any). DOCK7 knockdown with RNA interference blocked neuronal polarization and axon formation. Rac-dependent phosphorylation of Oncoprotein 18 (Op18 or stathmin) on serine-16 (Op18-S16-P) inhibits destabilization of microtubules by Op18. DOCK7 knockdown decreased Op18-S16-P in developing neurons, whereas DOCK7 overexpression enhanced Op18-S16-P. Op18-S16-P was enhanced in developing axons in vitro, and expression of a nonphosphorylatable mutant inhibited axon formation, as well as DOCK7-dependent induction of multiple axons. Thus, the authors propose that DOCK 7 regulates axon formation by means of Op18 regulation of microtubule dynamics.
M. Watabe-Uchida, K. A. John, J. A. Janas, S. E. Newey, L. Van Aelst, The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron 51, 727-739 (2006). [PubMed]
E. M. Pinheiro, F. B. Gertler, Nervous Rac: DOCK7 regulation of axon formation. Neuron 51, 674-676 (2006). [PubMed]