Reich-Erkelenz D.,University of Gottingen |
Schmitt A.,University of Gottingen |
Schmitt A.,University of Sao Paulo |
Gruber O.,University of Gottingen |
And 10 more authors.
Psychiatrie | Year: 2012
Over many years, intensive research into the molecular biological basis of psychosis (schizophrenia, bipolar disorder) has been conducted via complementary approaches of clinical and molecular biological techniques and strategies, be it linkage analyses, candidate gene association studies, pharmacogenetics, neuroimaging, or further neurobiological investigations in post-mortem tissue and animal models for risk factors of the diseases. However, since these approaches could not successfully explain the very heterogeneous disease pattern of schizophrenia or its overlapping spectra with bipolar disorder, we are in the need of a new perspective. Biological psychiatric research has largely focused on cross-sectional data sets without focusing on a phenotype of utmost relevance: the longitudinal course. Large-scale and systematic studies on the genetic and neurobiological underpinnings of the course of psychosis within a framework are lacking. To fill this gap, we are currently establishing such a framework via the DFG funded Clinical Research Group "Genotype-phenotype relationships and neurobiology of the longitudinal course of psychosis". Here we will establish large cohorts with this phenotype of interest that is longitudinal in nature and also includes information on functional parameters and environmental factors. © Schattauer GmbH.
Kannan M.,MPI of Experimental Medicine |
Lee S.-J.,MPI of Experimental Medicine |
Schwedhelm-Domeyer N.,MPI of Experimental Medicine |
Stegmuller J.,MPI of Experimental Medicine
Development (Cambridge) | Year: 2012
Axon growth is an essential event during brain development and is extremely limited due to extrinsic and intrinsic inhibition in the adult brain. The E3 ubiquitin ligase Cdh1-anaphase promoting complex (APC) has emerged as an important intrinsic suppressor of axon growth. In this study, we identify in rodents the E3 ligase Smurf1 as a novel substrate of Cdh1-APC and that Cdh1 targets Smurf1 for degradation in a destruction box-dependent manner. We find that Smurf1 acts downstream of Cdh1-APC in axon growth and that the turnover of RhoA by Smurf1 is important in this process. In addition, we demonstrate that acute knockdown of Smurf1 in vivo in the developing cerebellar cortex results in impaired axonal growth and migration. Finally, we show that a stabilized form of Smurf1 overrides the inhibition of axon growth by myelin. Taken together, we uncovered a Cdh1-APC/Smurf1/RhoA pathway that mediates axonal growth suppression in the developing mammalian brain. © 2012. Published by The Company of Biologists Ltd.