Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system

TY - JOUR

T1 - Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system

AU - Watanabe, Yasuhito

AU - Khodosevich, Konstantin

AU - Monyer, Hannah

N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2014/4/24

Y1 - 2014/4/24

N2 - 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.

AB - 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.

KW - Acetylation

KW - Anaphase-Promoting Complex-Cyclosome/metabolism

KW - Animals

KW - Cdc20 Proteins/metabolism

KW - Cell Cycle Proteins/metabolism

KW - Dendrites/metabolism

KW - Dentate Gyrus/cytology

KW - HEK293 Cells

KW - Histone Deacetylases/metabolism

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Neurogenesis

KW - Proteasome Endopeptidase Complex/metabolism

KW - Protein Binding

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Proteolysis

KW - Schizophrenia/genetics

KW - Tumor Suppressor Proteins/metabolism

U2 - 10.1016/j.celrep.2014.03.022

DO - 10.1016/j.celrep.2014.03.022

M3 - Journal article

C2 - 24726361

SN - 2211-1247

VL - 7

SP - 552

EP - 564

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -