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Thalheimer, F.B.* ; Wingert, S.* ; de Giacomo, P.* ; Haetscher, N.* ; Rehage, M.* ; Brill, B.* ; Theis, F.J. ; Hennighausen, L.* ; Schroeder, T.* ; Rieger, M.A.*

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

Stem Cell Rep. 3, 34-43 (2014)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Self-renewal; P38 Mapk; Stress; Kinase; Gadd45-gamma; Activation; Expansion
ISSN (print) / ISBN 2213-6711
Quellenangaben Volume: 3, Issue: 1, Pages: 34-43 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Maryland Heights, MO
Reviewing status Peer reviewed