Abstract
Although hematopoietic stem cells (HSCs) are the most thoroughly characterized type of adult stem cell, the intricate molecular machinery that regulates their self-renewal properties remains elusive. Here we showed that the E3 ubiquitin ligase Itch negatively regulated the development and function of HSCs. Itch−/− mice had HSCs with enhanced frequency, competence and long-term repopulating activity. Itch-deficient HSCs showed accelerated proliferation rates and sustained progenitor properties, as well as more signaling by the transcription factor Notch1, due to more accumulation of activated Notch1. Knockdown of Notch1 in Itch-mutant HSCs resulted in reversion of the phenotype. Thus, we identify Itch as a previously unknown negative regulator of HSC homeostasis and function.
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Acknowledgements
We thank F. Manzo for help with manuscript submission; and the Yale Cell Sorter Facility for support. Supported by the Howard Hughes Medical Institute (R.A.F.) and the administrative core of the National Institutes of Health Center for Biomedical Research Excellence at Roger Williams Medical Center (P20RR018757).
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C.R. conceived of, designed and did the study, analyzed and interpreted all data, and wrote the manuscript; L.E.M. provided the Itch−/− mice and corrected the manuscript; and R.A.F. provided advice and corrected the manuscript.
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Rathinam, C., Matesic, L. & Flavell, R. The E3 ligase Itch is a negative regulator of the homeostasis and function of hematopoietic stem cells. Nat Immunol 12, 399–407 (2011). https://doi.org/10.1038/ni.2021
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DOI: https://doi.org/10.1038/ni.2021
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