title: Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells.
abstract: The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.
authors: LOEWE Center for Cell and Gene Therapy and Department for Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Frederic B
authors: FB
authors: Thalheimer
authors: LOEWE Center for Cell and Gene Therapy and Department for Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Susanne
authors: S
authors: Wingert
authors: Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Pangrazio
authors: P
authors: De Giacomo
authors: LOEWE Center for Cell and Gene Therapy and Department for Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Nadine
authors: N
authors: Haetscher
authors: LOEWE Center for Cell and Gene Therapy and Department for Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Maike
authors: M
authors: Rehage
authors: Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Boris
authors: B
authors: Brill
authors: Institute of Computational Biology, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany ; Department of Mathematics, TU Munich, Boltzmannstrasse 3, 85747 Garching, Germany.
authors: Fabian J
authors: FJ
authors: Theis
authors: Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors: Lothar
authors: L
authors: Hennighausen
authors: Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors: Timm
authors: T
authors: Schroeder
authors: LOEWE Center for Cell and Gene Therapy and Department for Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany ; German Cancer Consortium (DKTK), Heidelberg, Germany ; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Michael A
authors: MA
authors: Rieger
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D000097642:GADD45 Proteins
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D000097642:GADD45 Proteins