title: Impaired functionality and homing of Fancg-deficient hematopoietic stem cells.
abstract: Fanconi anemia (FA) is a human rare genetic disorder characterized by congenital defects, bone marrow (BM) failure and predisposition to leukemia. The progressive aplastic anemia suggests a defect in the ability of hematopoietic stem cells (HSC) to sustain hematopoieis. We have examined the role of the nuclear FA core complex gene Fancg in the functionality of HSC. In Fancg-/- mice, we observed a decay of long-term HSC and multipotent progenitors that account for the reduction in the LSK compartment containing primitive hematopoietic cells. Fancg-/- lymphoid and myeloid progenitor cells were also affected, and myeloid progenitors show compromised in vitro functionality. HSC from Fancg-/- mice failed to engraft and to reconstitute at short and long term the hematopoiesis in a competitive transplantation assay. Fancg-/- LSK cells showed a loss of quiescence, an impaired migration in vitro in response to the chemokine CXCL12 and a defective homing to the BM after transplantation. Finally, the expression of several key genes involved in self-renewal, quiescence and migration of HSC was dysregulated in Fancg-deficient LSK subset. Collectively, our data reveal that Fancg should play a role in the regulation of physiological functions of HSC.
authors.affiliation: Laboratoire de Gamétogenèse Apoptose et Génotoxicite, Institut de Radiobiologie Cellulaire et Moléculaire, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses 92265, France.
authors.forename: Vilma
authors.initials: V
authors.lastname: Barroca
authors.forename: Marc André
authors.initials: MA
authors.lastname: Mouthon
authors.forename: Daniel
authors.initials: D
authors.lastname: Lewandowski
authors.forename: Philippe
authors.initials: P
authors.lastname: Brunet de la Grange
authors.forename: Laurent Robert
authors.initials: LR
authors.lastname: Gauthier
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: François Dominique
authors.initials: FD
authors.lastname: Boussin
authors.forename: Fre
authors.initials: F
authors.lastname: Arwert
authors.forename: Lydia
authors.initials: L
authors.lastname: Riou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Allemand
authors.forename: Paul Henri
authors.initials: PH
authors.lastname: Romeo
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouchet
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D052241:Fanconi Anemia Complementation Group G Protein / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D054377:Chemokine CXCL12; C499910:Fancg protein, mouse; D052241:Fanconi Anemia Complementation Group G Protein