Emerging roles of endoplasmic reticulum proteostasis in brain development

The development of the central nervous system requires a series of morphogenetic events that shape brain and spinal cord structures. Several brain regions and neural circuits are formed by differential gene expression patterns and cell migration events involving neurons. During neurogenesis and neuritogenesis, increased demand for protein synthesis occurs to express key neuronal proteins to generate axons, dendrites, and synapsis. The endoplasmic reticulum (ER) is a central hub controlling protein homeostasis (proteostasis), impacting a wide range of cellular processes required for brain function. Although most of the field has focused on studying the role of ER stress in neurodegenerative diseases marked by abnormal protein aggregation, accumulating evidence indicates that ER proteostasis contributes to brain development and may impact neurodevelopmental processes such as neuronal migration, differentiation, and function. Here, we review emerging evidence linking neurodevelopment with ER proteostasis and its relevance to human disorders. • Protein homeostasis at the endoplasmic reticulum (ER) is required for brain development and function. • Here, we review the function of ER folding pathways and the unfolded protein response (UPR) in brain development. • We focus on the differential impact on neuronal migration, differentiation, and function. • We discuss recent data supporting the relevance of ER proteostasis to brain function and neurodevelopmental diseases.