title: The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network.
abstract: Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta-4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, -D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and -2, as part of the stem signature associated with the Delta-4/Notch signalling pathway.
authors.affiliation: Inserm U974, CNRS (UMR 7215), UM 76, Institut de Myologie, Paris F-75013, France; Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France. Electronic address: c.catelain@institut-myologie.org.
authors.forename: Cyril
authors.initials: C
authors.lastname: Catelain
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Michelet
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Hattabi
authors.affiliation: Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Poirault-Chassac
authors.affiliation: CEA, 18 rue du Panorama, BP15, Fontenay-aux Roses, F92265, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Kortulewski
authors.affiliation: CEA, 18 rue du Panorama, BP15, Fontenay-aux Roses, F92265, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Tronik-Le Roux
authors.affiliation: Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lauret
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D053263:Gene Regulatory Networks; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D007399:Interphase; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D056741:Cyclin D; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D014157:Transcription Factors