(2011) reached a similar conclusion concerning the effect of Sema3A on axon development in the Xenopus model system. In vitro Sema3A treatment resulted in the conversion of Androgen Receptor antagonist neurites that would normally form axons into dendrites ( Nishiyama et al., 2011). The Nishiyama study

adds an additional piece to the puzzle by suggesting that Sema3A-induced cGMP signaling is able to induce expression of functional Cav2.3 channels ( Nishiyama et al., 2011). Expression of functional Cav2.3 channels was required for suppression of axonal development in vitro and for the appropriate acquisition of dendritic markers in vivo. Therefore, Sema3A may signal through a cGMP-mediated insertion of Cav2.3 channels to promote dendrite specification in addition to inhibiting axon specification. Is the position of the axon purely dictated by a lack of inhibitory factors, or is there

an extrinsic signal specifying axonal fate? Although BDNF could promote axon growth in vitro (Shelly et al., 2007 and Shelly et al., 2010), in vivo evidence supporting its role in axon specification remains to be shown. Other signaling molecules have somewhat stronger support. Netrin is required for the appropriate outgrowth of the only neurite of the HSN neuron in C. elegans ( Adler et al., 2006). In the absence of netrin (unc-6) or its receptor (unc-40), neurite outgrowth was delayed, and the process that did eventually emerge from the cell body was misguided ( Adler et al., 2006). Signaling through the TGF-β receptor, OSI-744 order TβR2, has recently been shown to be necessary for pyramidal axon formation in vivo ( Yi et al., 2010). A growing number of studies support the model that extrinsic signaling molecules can dictate the axon-dendrite polarity axis (Figure 1). While some molecules may promote axon outgrowth at the appropriate location, others such as Sema3A may Adenosine promote dendrite formation by inhibiting acquisition

of axonal fate. Other signals may be needed to help dictate appropriate dendrite outgrowth. The ability of neurons to break symmetry in vitro and the relatively low penetrance of in vivo phenotypes raise the possibility that these extrinsic cues may be redundant, with the internal polarizing pathways able to utilize a variety of extrinsic signals to dictate axon and dendrite outgrowth. As the signaling pathways regulating axon-dendrite polarity in vivo come into focus, it remains to be determined how these signals are spatially restricted or localized to effectively establish their cellular functions. Nonetheless, the study by Shelly et al. (2011) provides a novel framework within which to address these unresolved issues. “
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