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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.

SUBMITTER: Thalheimer FB 

PROVIDER: S-EPMC4110750 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells.

Thalheimer Frederic B FB   Wingert Susanne S   De Giacomo Pangrazio P   Haetscher Nadine N   Rehage Maike M   Brill Boris B   Theis Fabian J FJ   Hennighausen Lothar L   Schroeder Timm T   Rieger Michael A MA  

Stem cell reports 20140619 1


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  ...[more]

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