Non-cell-autonomous stimulation of stem cell proliferation following ablation of Tcf3.
A combination of cell intrinsic factors and extracellular signals determine whether mouse embryonic stem cells (ESC) divide, self-renew, and differentiate. Here, we report a new interaction between cell intrinsic aspects of the canonical Wnt/Tcf/beta-catenin signaling pathway and extracellular Lif/Jak/Stat3 stimulation that combines to promote self-renewal and proliferation of ESC. Mutant ESC lacking the Tcf3 transcriptional repressor continue to self-renew in the absence of exogenous Lif and through pharmacological inhibition of Lif/Jak/Stat3 signaling; however, proliferation rates of TCF3-/- ESC were significantly decreased by inhibiting Jak/Stat3 activity. Cell mixing experiments showed that stimulation of Stat3 phosphorylation in TCF3-/- ESC was mediated through secretion of paracrine acting factors, but did not involve elevated Lif or LifR transcription. The new interaction between Wnt and Lif/Jak/Stat3 signaling pathways has potential for new insights into the growth of tumors caused by aberrant activity of Wnt/Tcf/beta-catenin signaling.
Yi
Fei
F
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
Merrill
Bradley J
BJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D001562:Benzimidazoles; D053612:Janus Kinases; D053605:Leukemia Inhibitory Factor; D011728:Pyridones; D050796:STAT3 Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin; C524063:2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; C507838:Lif protein, mouse; C075668:Tcf3 protein, mouse