Katholieke University Leuven Center for Human Genetics

Leuven, Belgium

Katholieke University Leuven Center for Human Genetics

Leuven, Belgium
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PubMed | Psychiatry and., Umeå University, Juniata College, University of Antwerp and 3 more.
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of -secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate -secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the myelination hypothesis of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.


Pollarolo G.,Vlaams Instituut voor Biotechnologie | Pollarolo G.,Katholieke University Leuven Center for Human Genetics | Schulz J.G.,Vlaams Instituut voor Biotechnologie | Schulz J.G.,Katholieke University Leuven Center for Human Genetics | And 5 more authors.
Nature Neuroscience | Year: 2011

Polarization of a neuron begins with the appearance of the first neurite, thus defining the ultimate growth axis. Unlike late occurring polarity events (such as axonal growth), very little is known about this fundamental process. We show here that, in Drosophila melanogaster neurons in vivo, the first membrane deformation occurred 3.6 min after precursor division. Clustering of adhesion complex components (Bazooka (Par-3), cadherin-catenin) marked this place by 2.8 min after division; the upstream phosphatidylinositol 4,5-bisphosphate, by 0.7 min after division; and the furrow components RhoA and Aurora kinase, from the time of cytokinesis. Local DE-cadherin inactivation prevented sprout formation, whereas perturbation of division orientation did not alter polarization from the cytokinesis pole. This is, to our knowledge, the first molecular study of initial neuronal polarization in vivo. The mechanisms of polarization seem to be defined at the precursor stage. © 2011 Nature America, Inc. All rights reserved.


Degryse S.,Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease | Degryse S.,Katholieke University Leuven Center for Human Genetics | De Bock C.E.,Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease | De Bock C.E.,Katholieke University Leuven Center for Human Genetics | And 21 more authors.
Blood | Year: 2014

JAK3 is a tyrosine kinase that associates with the common g chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming propertiesofJAK3 pseudokinase and kinase domain mutants usinginvitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cellsinaJak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor bindingtomediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8+ T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL. © 2014 by The American Society of Hematology.


PubMed | University of Rome La Sapienza, University Ziekenhuizen, Katholieke University Leuven Center for Human Genetics and Erasmus University Rotterdam
Type: Journal Article | Journal: Blood | Year: 2014

JAK3 is a tyrosine kinase that associates with the common chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8(+) T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.


Dries D.R.,University of Texas Southwestern Medical Center | Dries D.R.,Juniata College | Zhu Y.,University of Texas Southwestern Medical Center | Brooks M.M.,University of Texas Southwestern Medical Center | And 15 more authors.
Journal of Biological Chemistry | Year: 2016

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessivecompulsive disorder is a distinct subtype of schizophrenia. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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