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. Source
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. Source