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The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders

Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as “Par complexes.” In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differentiation, synaptic plasticity, and memory. These versatile functions rely on the fundamental roles of Par complexes in cell polarity in distinct cellular contexts. We also discuss how cell polarization may correlate with subcellular polarization in neurons. Finally, we review the involvement of Par complexes in neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease. While emerging evidence indicates that Par complexes are essential for proper neural development and maintenance, many questions on their in vivo functions have yet to be answered. Thus, Par3, Par6, and aPKC continue to be important research topics to advance neuroscience.