Stem Cells

Pathways to Induction

Science Signaling  30 Jun 2009:
Vol. 2, Issue 77, pp. ec220
DOI: 10.1126/scisignal.277ec220

Cell fate specification relies on, among other factors, the sequence and timing of signaling events that direct cell type– or tissue-specific gene expression. Understanding the contribution of timing to the integration of developmental signals is important if researchers are to realize the ability to direct the specification of cells from stem cells for clinical use. Wandzioch and Zaret examined the interplay of bone morphogenetic protein (BMP), transforming growth factor–β (TGFβ), and fibroblast growth factor (FGF) signaling in endodermal cells that give rise to the liver and pancreas in the foregut endoderm of the mouse embryo. Using immunofluorescence with antibodies that recognize activated mediators of these signaling pathways, the authors demonstrated that at the 3–4 and 5–6 somite (S) stages, cells in the lateral portions of the prospective hepatocyte progenitor domain were positive for mitogen-activated protein kinase (MAPK, which is activated downstream of FGF) activity and BMP-negative for BMP activity, whereas the ventral-medial portion was MAPK-negative and BMP-positive. As the lateral cells migrated ventrally, the entire hepatocyte progenitor population became positive for both MAPK and BMP signaling at the 7–9S stage, which suggested that fate specification is plastic enough that cells with different histories may adopt equivalent fates. Genetics and embryo culture experiments indicated that BMP signaling repressed the pancreatic progenitor fate at early stages of development (3–4S) but promoted expression of pancreatic markers at later (5–6S and 7–9S) stages. Both TGFβ and FGF signaling repressed pancreatic cell fate in the lateral part of the foregut endoderm field, thus ensuring that pancreatic cells were not specified until they migrated to their proper position ventral and caudal to the liver progenitors, where they responded to BMP signaling by activating expression of pancreas markers. These findings highlight the importance of parallel inputs in cell fate determination and offer a plausible explanation for the common problem of incomplete specification in stem cell derivatives.

E. Wandzioch, K. S. Zaret, Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324, 1707–1710 (2009). [Abstract] [Full Text]