Endosomal protein DENND10 promotes developmental competence of neurite extension

A distinguishing feature of neurons is the presence of long neurites that enable far-reaching communication. Establishing this complex morphology requires precise regulation of intracellular transport and signaling. Our study identifies DENND10, an ancient endosomal protein, as a crucial factor in shaping neuron morphology. DENND10 is a potential regulator of Rab GTPase signaling and interacts with the CCC/Retriever endosomal complex. Loss of DENND10 in a neuronal cell culture model resulted in shortened neurites. Quantitative proteomics revealed two distinct processes of neurite outgrowth: differentiation-induced biochemical changes and a pre-existing vesicular transport system modulated by DENND10. Mechanistically, both Rab27 and CCC complex subunit CCDC22 act downstream of DENND10 to support neurite extension. In primary cortical neurons, loss of DENND10 or CCDC22 led to shortened dendrites and impaired axon development. These findings provide a conceptual framework for neuronal morphogenesis during differentiation and highlight the critical role of DENND10/CCC in neurite extension.