title: Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system.
abstract: Downregulation of the schizophrenia-associated gene DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion.
authors.affiliation: Department of Clinical Neurobiology at the German Cancer Research Center (DKFZ) and the Medical Faculty of Heidelberg University, Heidelberg 69120, Germany.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Neurobiology at the German Cancer Research Center (DKFZ) and the Medical Faculty of Heidelberg University, Heidelberg 69120, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khodosevich
authors.affiliation: Department of Clinical Neurobiology at the German Cancer Research Center (DKFZ) and the Medical Faculty of Heidelberg University, Heidelberg 69120, Germany. Electronic address: h.monyer@dkfz-heidelberg.de.
authors.forename: Hannah
authors.initials: H
authors.lastname: Monyer
mesh_terms: D000107:Acetylation; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D064199:Cdc20 Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis; D012559:Schizophrenia / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C584278:Bub1b protein, mouse; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; C574993:Lzts1 protein, mouse; D025521:Tumor Suppressor Proteins; D064173:Anaphase-Promoting Complex-Cyclosome; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; C528111:Hdac11 protein, mouse; D006655:Histone Deacetylases