, 2008; B.N.L., unpublished data). We favor the idea that multiple,

redundant kinases perform SAD ALT phosphorylation in DRG neurons, but their ability to access the SAD ALT is dependent upon SAD CTD dephosphorylation. In this scenario, ALT phosphorylation is regulated not by limited availability of an ALT kinase but by CTD-dependent accessibility of the ALT site. In addition to regulating the activation state of SAD kinases, phosphorylation of the CTD may also play a role in stabilizing the protein: removing the 18 sites of CTD phosphorylation around the D box consistently decreased protein levels in cell lines and in neurons (Figure 6 and data not shown). Phosphorylation of the SAD CTD around the D box could stabilize the protein by inhibiting interaction with the APC/C, a mechanism similar to that learn more described for the control of securin ubiqutination during anaphase (Holt et al., 2008). Dephosphorylation of the CTD in response to NT-3 could then result in targeting

of SADs for degradation, thus extinguishing signals Compound C cost from SADs in the activated, dephospho-CTD form (Figure 8G). In the telencephalon, LKB1 and SADs control early axon-dendrite polarization and axon formation (Kishi et al., 2005, Barnes et al., 2007 and Shelly et al., 2007). Here, we have shown that SADs affect axonal arborization in some sensory neurons. Initial studies of the C. elegans SAD ortholog, SAD-1, demonstrated a role for this kinase in presynaptic differentiation ( Crump et al., 2001), and we found recently that SADs are required for maturation of multiple synaptic types in mouse central and peripheral nervous systems (B.N.L. STK38 and J.R.S., unpublished data). Finally, Inoue et al. (2006) have reported that SADs modulate presynaptic function in adults. Together, these

studies establish SAD kinases as essential regulators of multiple phases of axonal development and function. A major outstanding question is how SAD kinases activate programs that influence multiple processes of axonal development. While we cannot rule out possible kinase-independent roles of SAD kinases, at least in C. elegans, kinase activity is essential for SAD function in vivo ( Crump et al., 2001 and Kim et al., 2008), suggesting that substrate phosphorylation is the key functional output. However, only a few SAD substrates have been identified so far, including the microtubule-associated proteins Tau, the cell cycle regulators Wee1 and Cdc25, gamma-tubulin and the nerve terminal component RIM ( Barnes et al., 2007, Inoue et al., 2006, Lu et al., 2004, Müller et al., 2010 and Alvarado-Kristensson et al., 2009). Determining how SAD kinases shape neuronal form and connectivity will require examination of how these kinases process upstream signals in distinct developmental contexts and how downstream phosphorylation modifies the activity of yet-to-be-identified substrates.