Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration.
Interactions between developmental signaling pathways govern the formation and function of stem cells. Prostaglandin (PG) E2 regulates vertebrate hematopoietic stem cells (HSC). Similarly, the Wnt signaling pathway controls HSC self-renewal and bone marrow repopulation. Here, we show that wnt reporter activity in zebrafish HSCs is responsive to PGE2 modulation, demonstrating a direct interaction in vivo. Inhibition of PGE2 synthesis blocked wnt-induced alterations in HSC formation. PGE2 modified the wnt signaling cascade at the level of beta-catenin degradation through cAMP/PKA-mediated stabilizing phosphorylation events. The PGE2/Wnt interaction regulated murine stem and progenitor populations in vitro in hematopoietic ES cell assays and in vivo following transplantation. The relationship between PGE2 and Wnt was also conserved during regeneration of other organ systems. Our work provides in vivo evidence that Wnt activation in stem cells requires PGE2, and suggests the PGE2/Wnt interaction is a master regulator of vertebrate regeneration and recovery.
Goessling
Wolfram
W
Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
North
Trista E
TE
Loewer
Sabine
S
Lord
Allegra M
AM
Lee
Sang
S
Stoick-Cooper
Cristi L
CL
Weidinger
Gilbert
G
Puder
Mark
M
Daley
George Q
GQ
Moon
Randall T
RT
Zon
Leonard I
LI
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D015232:Dinoprostone / Q000378:metabolism*; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008099:Liver / Q000502:physiology; D051379:Mice; D012038:Regeneration; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin; D015232:Dinoprostone