Cullin-RING E3 ubiquitin ligase 4 controls axonal morphogenesis during neuronal development

Abstract

Abstract Neuritogenesis is critical for the establishment of proper neuronal connections during brain development. Thus, its failure causes neurodevelopmental defects such as intellectual disabilities. Cullin-RING E3 ubiquitin-ligase complexes are involved in neurodevelopmental processes including neurite outgrowth, migration, and differentiation via regulation of protein stability. In this study, we demonstrate a novel regulatory function of Cullin-RING E3 ubiquitin-ligase 4 (CRL4) in neurite morphogenesis during early neurodevelopment. Cul4a and Cul4b, core scaffold proteins of CRL4, are highly expressed and activated in the cytosolic compartment of developing neuron, and they are regulated by neuronal stimulation via N-methyl D-aspartate (NMDA) receptor signaling. CRL4 also interacts with cytoskeleton-regulating proteins involved in neurite morphogenesis in neurons. Notably, CRL4 inhibition enhances axonal extension and branching in developing neurons. Conversely, Cul4a overexpression suppresses basal and NMDA-enhanced axonal outgrowth. Furthermore, CRL4 regulates the stability of Doublecortin protein recruited by Cereblon. Taken together, we suggest a novel role of CRL4 in proper axonal morphogenesis in developing neurons by regulating cytoskeleton-regulating proteins.