title: Hepatocyte Nuclear Factor 1A Is a Cell-Intrinsic Transcription Factor Required for B Cell Differentiation and Development in Mice.
abstract: The hepatocyte NF (HNF) family of transcription factors regulates the complex gene networks involved in lipid, carbohydrate, and protein metabolism. In humans, HNF1A mutations cause maturity onset of diabetes in the young type 3, whereas murine HNF6 participates in fetal liver B lymphopoiesis. In this study, we have identified a crucial role for the prototypical member of the family HNF1A in adult bone marrow B lymphopoiesis. HNF1A(-/-) mice exhibited a clear reduction in total blood and splenic B cells and a further pronounced one in transitional B cells. In HNF1A(-/-) bone marrow, all B cell progenitors-from pre-pro-/early pro-B cells to immature B cells-were dramatically reduced and their proliferation rate suppressed. IL-7 administration in vivo failed to boost B cell development in HNF1A(-/-) mice, whereas IL-7 stimulation of HNF1A(-/-) B cell progenitors in vitro revealed a marked impairment in STAT5 phosphorylation. The B cell differentiation potential of HNF1A(-/-) common lymphoid progenitors was severely impaired in vitro, and the expression of the B lymphopoiesis-promoting transcription factors E2A, EBF1, Pax5, and Bach2 was reduced in B cell progenitors in vivo. HNF1A(-/-) bone marrow chimera featured a dramatic defect in B lymphopoiesis recapitulating that of global HNF1A deficiency. The HNF1A(-/-) lymphopoiesis defect was confined to B cells as T lymphopoiesis was unaffected, and bone marrow common lymphoid progenitors and hematopoietic stem cells were even increased. Our data demonstrate that HNF1A is an important cell-intrinsic transcription factor in adult B lymphopoiesis and suggest the IL-7R/STAT5 module to be causally involved in mediating its function.
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Karin
authors.initials: K
authors.lastname: von Wnuck Lipinski
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Katherine
authors.initials: K
authors.lastname: Sattler
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Susann
authors.initials: S
authors.lastname: Peters
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Weske
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany; and.
authors.forename: Hannes
authors.identifier: http://orcid.org/0000-0003-3536-1212
authors.initials: H
authors.lastname: Klump
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany;
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.affiliation: Department of Hematology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Joachim R
authors.identifier: http://orcid.org/0000-0001-8957-6732
authors.initials: JR
authors.lastname: Göthert
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, 45122 Essen, Germany; bodo.levkau@uni-due.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000276:immunology*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D014157:Transcription Factors