K. and by the Friedrich Schiedel Foundation. A.K. is a Carl von Linde Senior Fellow of the Institute for Advanced Study of the Technische Universität München. N.L.R. was supported by the DFG (IRTG 1373). M.N. was supported

by the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad. “
“The polarized architecture of axon and dendrites is critical for the neuron to function as a computational unit in the nervous system. During early development, the initial establishment of axon/dendrite polarity may depend on intrinsic determinants within the neuron and extrinsic factors from its environment (Arimura and Kaibuchi, 2007 and Barnes et al., 2008). The intrinsic determinant may accumulate asymmetrically in the cytoplasm as a result of the last mitotic division (de Anda et al., 2005) or selleck chemicals llc a self-amplification process (Arimura and Kaibuchi, 2007 and Shelly et al., 2007) that acts upon local stochastic fluctuation of its distribution or activity (Jacobson et al., 2006), leading to axon/dendrite differentiation. Many extrinsic factors, including gradients of diffusible or bound chemical factors in the developing tissue, may polarize the neuron by setting the axis of the asymmetric division, the direction of axon/dendrite initiation from the soma, and the morphology and orientation of axonal and dendritic arbors (Polleux et al., 1998, Polleux et al., 2000, Noctor et al., IWR1 2004, Adler et al.,

2006, Hilliard and Bargmann, 2006 and Yi et al., 2010). In this study, we focused on the role of Sema3A, a secreted protein of the class III semaphorin superfamily, in axon/dendrite initiation during the early phase of neuronal polarization, prior to its effects as a chemotropic factor for axon/dendrite guidance (Polleux et al., 2000) and neuronal migration (Chen et al., 2008). In the absence of asymmetric extrinsic cues, dissociated embryonic hippocampal neurons undergo aminophylline spontaneous polarization in culture—from a cell exhibiting several morphologically similar neurites to a mature neuron exhibiting a single axon and multiple dendrites within few days and capable of forming functional synapses within 1–2 weeks (Dotti

and Banker, 1987 and Dotti et al., 1988). Using this culture system, previous studies have shown that local activation of either PI3-kinase (Shi et al., 2003 and Yoshimura et al., 2005) or cAMP/PKA (Shelly et al., 2007 and Shelly et al., 2010) signaling pathways can trigger axon differentiation, through recruitment or phosphorylation of proteins such as plasma membrane ganglioside sialidase (PMGS) (Da Silva et al., 2005), shootin1 (Toriyama et al., 2006), and LKB1 (Barnes et al., 2007 and Shelly et al., 2007). These proteins in turn regulate downstream effectors, such as the PAR3/PAR6/aPKC complex (Shi et al., 2003), GSK-3β (Yoshimura et al., 2005), Rho family of small GTPases (Schwamborn and Püschel, 2004), and CRMP2 (Inagaki et al.