Defining the role of 14-3-3ζ in neuronal migration and neurogenesis

Abstract

Neuropsychiatric disorders such as schizophrenia have complex genetic traits and are believed to arise from defects in multiple genes within connected biological networks. One of the major limitations regarding the neurobiology of higher brain function and in studying complex psychiatric disorders is the necessity to use animal models to mimic the higher complexity of the human brain. Recently, 14-3-3ζ has been associated with schizophrenia and our laboratory has previously demonstrated that mice lacking this gene have deficits reminiscent of the human condition. This thesis provides further evidence for 14-3-3ζ KO mice representing a unique and appropriate model to study the aetiology of schizophrenia and related disorders, with core focus on the orchestrated development of hippocampal neurons. Some of the key findings include; 1) the importance of 14-3-3ζ in controlling neuronal migration to promote hippocampal lamination, 2) the importance of 14-3-3ζ in controlling axonal pathfinding and dendritic spine formation, 3) the direct interaction of 14-3-3ζ with Cdk5/p35 phosphorylated Ndel1 to maintain Ndel1 phosphorylation and promote neuronal migration, and 4) the role of 14-3-3ζ in embryonic, early postnatal and adult neurogenesis, particularly in neural stem/progenitor cells proliferation and self-renewal. Taken together, this work provides novel insight to the functions of 14-3-3ζ in neuronal development and the aetiology of neuropsychiatric disorders.