Novel Functions of 14-3-3 Proteins in Neurogenesis and Neuronal Differentiation In Vivo

Abstract

During brain development, there are many essential steps for the proper formation of a functional brain, including neurogenesis and neuronal migration. Neuronal progenitor cells (NPCs) proliferate and symmetrically divide to expand their pools in the developing cerebral cortex. NPCs also asymmetrically divide to produce one neuronal progenitor cell and one neuron. These newly-born post-mitotic neurons radially migrate and reach the final destination in the cortical plate (CP) to finally form the six layers of the cortex. We previously found that the protein 14-3-3epsilon is important for neuronal migration and a responsible gene for the development of Miller-Dieker syndrome (MDS). Although fortunately we found the neuronal migration defects in 14-3-3epsilon knockout mice, there may be functional redundancies because there are seven isoforms in the family of 14-3-3 proteins, with high homology among them. Therefore, we produced the 14-3-3epsilon and 14-3-3zeta double knockout mice (14-3-3 dKO mice) and found that the dKO mice showed spontaneous epilepsy. We also found novel in vivo functions of the 14-3-3epsilon and 14-3-3zeta proteins in neurogenesis of radial glial cells (RGCs) as well as intermediate progenitor cells (IPCs) and in neuronal differentiation. In addition to the pathological defects seen in the dKO mice, we identified the molecular mechanisms involved in the neuronal differentiation defects and showed that the binding of 14-3-3 proteins to d-catenin proteins regulated actin dynamics. Thus, 14-3-3 proteins are important for the key steps of brain development, including neurogenesis, neuronal migration and neuronal differentiation as well as their involvement and involved in various brain morphological disorders, such as epilepsy.