Functional Roles And Regulation Of The Guanine Nucleotide Exchange Factor Dock4in Neurite Differentiation

Precise regulation of neurite growth and differentiation determines accurate formation ofsynaptic connections, whose disruptions are frequently associated with neurological disorders.Previous studies show that dedicator of cytokinesis4(Dock4), an atypical guanine nucleotideexchange factor (GEF) for Rac1, is found to be associated with neuropsychiatric diseasesincluding autism and schizophrenia. Nonetheless, the neuronal function of Dock4has beenunclear thus far. In this study, we found that Dock4was highly expressed in the developing ratbrain, predominantly in hippocampal neurons and the expression of Dock4was increased as thedevelopment and maturation of rat. In primary cultured hippocampal neurons, the expression ofDock4was up-regulated starting from7days of in vitro (DIV), when dendrites began to grow.Using mouse neuroblastoma (Neuro-2a) cells as a model, we identify that Dock4is critical forneurite differentiation and extension induced by retinoic acid (RA). This regulation is throughactivation of Rac1and modulation of the dynamics of actin-enriched protrusions on the neurites.Further analysis reveals that the SH3domain and the DHR2domain (GEF domain) of Dock4areboth required for its activity towards neurite outgrowth, whereas its proline-rich C-terminus isnot essential for this regulation. Importantly, we show that Dock4regulates both theestablishment of the axon-dendrite polarization and the arborization of dendrites in culturedhippocampal neurons. Together, our findings reveal an important role of Dock4for neuritedifferentiation and dendrite morphogenesis during early neuronal development.