A Critical Role of cTAGE5/MEA6 in Brain Development through Regulation of Trafficking of Cellular Components in Neurons

Normal neural development is essential for the formation of neuronal networks and brain function. cTAGE5/MEA6 plays a critical role in the secretion of proteins. However, its roles in the transport of non-secretory cellular components and in brain development remain unknown. Here, we show that cTAGE5/MEA6 is essential for brain development and function. Conditional knockout of cTAGE5/MEA6 in the brain leads to severe defects in neural development, including deficits in dendrite outgrowth and branching, synapse formation and/or maintenance, astrocyte activation, and abnormal behaviors. We reveal that loss of cTAGE5/MEA6 affects the interaction between the coat protein complex II (COPII) components, SAR1 and SEC23, leading to persistent activation of SAR1 and defects in COPII vesicle formation and transport from the ER to Golgi, as well as disturbed trafficking of membrane components in neurons. These defects affect not only the transport of materials required for the development of dendrites and spines, but also the signaling pathways required for neuronal development. Since mutations in cTAGE5/MEA6 have been found in patients with Fahr’s disease, our study potentially also provides insight into the pathogenesis of this disorder.