, 2005, Ménager et al., 2004, Shi et al., 2003, Sosa et al., 2006 and Yoshimura et al., 2006), raising a potential paradox of how the FOXO transcription factors, which are inhibited by the PI3K-Akt signaling pathway, promote neuronal polarization. It remains unclear, however, whether localized Akt signaling in Perifosine price the axon influences the activity

of the FOXO transcription factors in the nucleus. Notably, growth factor inhibition of FOXO proteins can be countered in cellular contexts whereby the protein kinases MST1, JNK, and AMPK promote the nuclear accumulation of FOXO proteins and thereby induce FOXO-dependent transcription (Essers et al., 2004, Greer et al., 2007 and Lehtinen et al., 2006). It will

be interesting to determine if these or other signals stimulate FOXO-dependent transcription in neuronal polarization. There has been much interest in the specific biological roles of different FOXO family members. The FOXO proteins are expressed in overlapping patterns in the brain and other tissues and appear to bind to similar sites within responsive genes XAV-939 mw (Furuyama et al., 2000 and Hoekman et al., 2006). Accordingly, the FOXO transcription factors have redundant roles as tumor suppressors in hematopoietic stem cells in vivo (Paik et al., 2007 and Tothova et al., 2007). However, genetic ablation of different FOXO Ketanserin family members in mice results in distinct phenotypes in vivo (Castrillon et al., 2003, Furuyama et al., 2004, Hosaka et al., 2004, Kitamura et al., 2002, Lin et al., 2004, Nakae et al., 2002, Polter et al., 2009 and Renault

et al., 2009), suggesting specific roles for individual family members. The FOXO proteins FOXO1, FOXO3, and FOXO6 appear to operate redundantly in driving neuronal polarization (de la Torre-Ubieta et al., 2010). However, in rescue experiments in the background of FOXO RNAi, expression of FOXO1 or FOXO3 only partially restores polarity, whereas expression of FOXO6 substantially restores polarity. Therefore, FOXO6 may have some nonoverlapping functions in neuronal polarity. It will be important in the future to characterize the transcriptional targets of individual FOXO family members to understand the contribution of each FOXO protein to neuronal polarity. Neuronal polarization temporally overlaps with radial migration in certain populations of neurons in the mammalian brain. In the developing cerebral cortex, cortical neurons undergo a transition from a multipolar to bipolar morphology as they leave the intermediate zone (IZ) and move toward the cortical plate, and this morphological transition is regarded as polarization in cortical neurons (Calderon de Anda et al., 2008, Noctor et al., 2004 and Tabata and Nakajima, 2003).