cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development

Abstract

<p id="d5569261e431">Neural development is essential for the formation of neuronal networks and brain function. cTAGE5/MEA6 plays a critical role in the secretion of proteins, including very low density lipoprotein and insulin; however, its role in the transport of cellular (nonsecretory) components and in brain development has not been previously explored. Here, we show that cTAGE5/MEA6 is essential for neural development, and knockout of cTAGE5/MEA6 in the mouse brain leads to severe neural developmental defects. The underlying mechanisms for the role of cTAGE5/MEA6 in brain development have been explored in this study. Interestingly, mutations in cTAGE5/MEA6 have been found in patients with Fahr’s disease. Thus, our study also provides insight into the possible pathogenesis mechanisms of this neurological disorder. </p><p class="first" id="d5569261e434">Normal neural development is essential for the formation of neuronal networks and brain function. Cutaneous T cell lymphoma-associated antigen 5 (cTAGE5)/meningioma expressed antigen 6 (MEA6) plays a critical role in the secretion of proteins. However, its roles in the transport of nonsecretory cellular components and in brain development remain unknown. Here, we show that cTAGE5/MEA6 is important for brain development and function. Conditional knockout of <i>cTAGE5/MEA6</i> in the brain leads to severe defects in neural development, including deficits in dendrite outgrowth and branching, spine formation and 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 endoplasmic reticulum to the 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. Because 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. </p>