Members of the semaphorin family of proteins also mediate attractive signaling. Chemoattractive signaling effected, for instance, via Netrin-1 through its receptors deleted in colorectal cancer (DCC) and Down’s syndrome cell adhesion molecule (DSCAM), is responsible for the attraction of commissural axons toward the midline in the spinal cord ( Kennedy et al., 1994 Serafini et al., 1994 Keino-Masu et al., 1996 Ly et al., 2008). Guidance cues are broadly classified into attractive and repulsive cues. While this requires coordination between guidance cue signaling and intracellular transport pathways, how this synchronization is achieved remains poorly understood. Extension and branching of these processes as they migrate toward their final destinations are critically dependent on the delivery and insertion of new biomolecules at the elongation sites ( Pfenninger, 2009). Guidance cue-dependent navigation of neuronal processes to their cellular targets contributes to the formation of neuronal networks during brain development ( Kim and Chiba, 2004 Kolodkin and Tessier-Lavigne, 2011). Taken together, these findings highlight the importance of FEZ1 as a common effector to integrate guidance signaling pathways with intracellular trafficking to mediate axo-dendrite development during neuronal network formation. Significantly, developing axons and dendrites of FEZ1-deficient neurons fail to respond to Netrin-1 or Netrin-1 and Sema3A treatment, respectively. Supporting this, FEZ1 colocalizes with VAMP2 in developing hippocampal neurons and forms a separate complex with deleted in colorectal cancer (DCC) and Syntaxin-1 (Stx1), components of the Netrin-1 signaling pathway that are also involved in regulating axon and dendrite development. Strikingly, FEZ1-deficient neurons also exhibited a reduction in dendritic complexity stronger than that observed in CRMP1-deficient neurons, suggesting that the former could partake in additional developmental signaling pathways. We show that similar to CRMP1 loss-of-function mutants, FEZ1 deficiency in rat hippocampal neurons causes growth cone collapse and impairs axonal development. Here, we characterize an interaction between fasciculation and elongation protein zeta 1 (FEZ1), an adapter involved in synaptic protein transport, and collapsin response mediator protein (CRMP)1, a protein that functions in growth cone guidance, at neuronal growth cones. However, how such coordination is achieved remains incompletely understood. Guidance cues must work closely with intracellular trafficking pathways to direct expanding axons and dendrites to their target neurons during the formation of neuronal networks. Elaboration of neuronal processes is an early step in neuronal development.
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