FEZ1 forms complexes with CRMP1 and DCC to regulate axon and dendrite development


  • J.Y. Chua
  • S.J. Ng
  • O. Yagensky
  • E.E. Wanker
  • J.J.E. Chua


  • eNeuro


  • eNeuro 8 (2): ENEURO.0193-20.2021


  • Elaboration of neuronal processes is an early step in neuronal development. 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. However, how such coordination is achieved remains incompletely understood. Here, we characterize an interaction between FEZ1, an adapter involved in synaptic protein transport, and CRMP1, a protein that functions in growth cone guidance, at neuronal growth cones. We show that similar to CRMP1 loss-of-function mutants, FEZ1 deficiency in rat hippocampal neurons causes growth cone collapse and impairs axonal 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. Supporting this, FEZ1 colocalizes with VAMP2 in developing hippocampal neurons and forms a separate complex with Deleted in Colorectal Cancer and Syntaxin-1, components of the Netrin-1 signaling pathway that are also involved in regulating axon and dendrite development. Significantly, developing axons and dendrites of FEZ1-deficient neurons fail to respond to Netrin-1 or Netrin-1 and Sema3A treatment, respectively. 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. SIGNIFICANCE STATEMENT: Guidance cue-dependent elaboration of axons and dendrites towards their target neurons is a critical step in the formation of neuronal circuits during brain development. The elongating neurites require a constant supply of biomolecules, but it remains unclear how guidance cues cooperate with intracellular transport. Here, we show that the kinesin-1 adapter FEZ1 forms complexes with CRMP1 or DCC, which are downstream effectors of the Sema3A and Netrin-1 signaling pathway, respectively. FEZ1-deficient neurons not only exhibit abnormal axons and dendrites, they were also unresponsive to Sema3A- or Netrin-1-dependent regulation of axo-dendritic development. Our results highlight FEZ1 as a key convergence point where guidance cues and intracellular transport integrate to coordinate neuronal process development during neuronal network formation.