セミナー情報

Downregulation of the schizophrenia associated genes Disrupted-in Schizophrenia 1 (DISC1) and its interacting protein Fasciculation and Elogatiaon Protein Zeta-1 (FEZ1) positively regulate dendrite growth in young neurons. However, little is known about the mechanism by which these schizophrenia risk factor genes control neuronal development. Here we identified several components of the ubiquitin proteasome system and the cell cycle machinery that act upstream of FEZ1. Thus, we demonstrate that the ubiquitin ligase Anaphase-Promoting Complex (APC) and the coactivator Cell division cycle 20 (Cdc20) complex controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by Budding uninhibited by benzymidazole 1-related protein kinase (BuBR1), a regulator of Cdc20/APC, whose known function so far was restricted to control mitosis in cycling cells. Of note, the modulatory function BubR1 is dependent on its acetylation status. Its deacetylation by Histone deacetylase 11 (Hdac11) disinhibits the Cdc20/APC complex. Since dendrite growth was affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism regulating FEZ1 expression governs neuronal development in a general fashion.