title: Prep1 (pKnox1) regulates mouse embryonic HSC cycling and self-renewal affecting the Stat1-Sca1 IFN-dependent pathway.
abstract: A hypomorphic Prep1 mutation results in embryonic lethality at late gestation with a pleiotropic embryonic phenotype that includes defects in all hematopoietic lineages. Reduced functionality of the hematopoietic stem cells (HSCs) compartment might be responsible for the hematopoietic phenotype observed at mid-gestation. In this paper we demonstrate that Prep1 regulates the number of HSCs in fetal livers (FLs), their clonogenic potential and their ability to de novo generate the hematopoietic system in ablated hosts. Furthermore, we show that Prep1 controls the self-renewal ability of the FL HSC compartment as demonstrated by serial transplantation experiments. The premature exhaustion of Prep1 mutant HSCs correlates with the reduced quiescent stem cell pool thus suggesting that Prep1 regulates the self-renewal ability by controlling the quiescence/proliferation balance. Finally, we show that in FL HSCs Prep1 absence induces the interferon signaling pathway leading to premature cycling and exhaustion of fetal HSCs.
authors.affiliation: Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Modica
authors.affiliation: Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iotti
authors.affiliation: Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: D'Avola
authors.affiliation: Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000818:Animals; D017209:Apoptosis; D000067696:Ataxin-1 / Q000378:metabolism; D001483:Base Sequence; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D007372:Interferons / Q000502:physiology; D008099:Liver / Q000166:cytology; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D018398:Homeodomain Proteins; C491412:Pknox1 protein, mouse; D050794:STAT1 Transcription Factor; D051785:Smad Proteins; C494080:Stat1 protein, mouse; D007372:Interferons