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    Cell competition is a tumour suppressor mechanism in the thymus (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-16
    Description: Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martins, Vera C -- Busch, Katrin -- Juraeva, Dilafruz -- Blum, Carmen -- Ludwig, Carolin -- Rasche, Volker -- Lasitschka, Felix -- Mastitsky, Sergey E -- Brors, Benedikt -- Hielscher, Thomas -- Fehling, Hans Joerg -- Rodewald, Hans-Reimer -- England -- Nature. 2014 May 22;509(7501):465-70. doi: 10.1038/nature13317. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany [2] Institute of Immunology, University of Ulm, D-89081 Ulm, Germany. ; Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany. ; Institute of Immunology, University of Ulm, D-89081 Ulm, Germany. ; Core Facility Small Animal MRI, University of Ulm, D-89081 Ulm, Germany. ; Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828041" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cell Movement ; *Cell Transformation, Neoplastic/genetics ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; HMGA Proteins/genetics ; Hematopoietic Stem Cells/*cytology/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/*pathology ; Receptor, Notch1/genetics ; T-Lymphocytes/cytology/metabolism/pathology ; Thymus Gland/*cytology/pathology ; Transcriptome/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration (2015)
    Oxford University Press
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    Publication Date: 2015-03-20
    Description: Mutations in components of the molecular motor dynein/dynactin lead to neurodegenerative diseases of the motor system or atypical parkinsonism. These mutations are associated with prominent accumulation of vesicles involved in autophagy and lysosomal pathways, and with protein inclusions. Whether alleviating these defects would affect motor symptoms remain unknown. Here, we show that a mouse model expressing low levels of disease linked-G59S mutant dynactin p150 Glued develops motor dysfunction 〉8 months before loss of motor neurons or dopaminergic degeneration is observed. Abnormal accumulation of autophagosomes and protein inclusions were efficiently corrected by lowering dietary protein content, and this was associated with transcriptional upregulations of key players in autophagy. Most importantly this dietary modification partially rescued overall neurological symptoms in these mice after onset. Similar observations were made in another mouse strain carrying a point mutation in the dynein heavy chain gene. Collectively, our data suggest that stimulating the autophagy/lysosomal system through appropriate nutritional intervention has significant beneficial effects on motor symptoms of dynein/dynactin diseases even after symptom onset.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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