title: The E3 ligase Itch is a negative regulator of the homeostasis and function of hematopoietic stem cells.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Chozhavendan
authors.initials: C
authors.lastname: Rathinam
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Matesic
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000276:immunology; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000276:immunology; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051881:Receptor, Notch1 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination
chemical_list: C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases