title: Fancd2 is required for nuclear retention of Foxo3a in hematopoietic stem cell maintenance.
abstract: Functional maintenance of hematopoietic stem cells (HSCs) is constantly challenged by stresses like DNA damage and oxidative stress. Here we show that the Fanconi anemia protein Fancd2 and stress transcriptional factor Foxo3a cooperate to prevent HSC exhaustion in mice. Deletion of both Fancd2 and Foxo3a led to an initial expansion followed by a progressive decline of bone marrow stem and progenitor cells. Limiting dilution transplantation and competitive repopulating experiments demonstrated a dramatic reduction of competitive repopulating units and progressive decline in hematopoietic repopulating ability of double-knockout (dKO) HSCs. Analysis of the transcriptome of dKO HSCs revealed perturbation of multiple pathways implicated in HSC exhaustion. Fancd2 deficiency strongly promoted cytoplasmic localization of Foxo3a in HSCs, and re-expression of Fancd2 completely restored nuclear Foxo3a localization. By co-expressing a constitutively active CA-FOXO3a and WT or a nonubiquitinated Fancd2 in dKO bone marrow stem/progenitor cells, we demonstrated that Fancd2 was required for nuclear retention of CA-FOXO3a and for maintaining hematopoietic repopulation of the HSCs. Collectively, these results implicate a functional interaction between the Fanconi anemia DNA repair and FOXO3a pathways in HSC maintenance.
authors.affiliation: From the Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: the Department of Neurosurgery, University of California, San Diego, La Jolla, California 92093.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.affiliation: From the Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Jared
authors.initials: J
authors.lastname: Sipple
authors.affiliation: From the Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schick
authors.affiliation: From the Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and qishen.pang@cchmc.org.
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005269:Femur / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D013977:Tibia / Q000378:metabolism
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse
keywords: DNA Damage; DNA Repair; FOXO; Fancd2; Hematopoietic Stem Cells; Oxidative Stress