Prolonged FGF signaling is necessary for lung and liver induction in Xenopus

Abstract

BackgroundFGF signaling plays numerous roles during organogenesis of the embryonic gut tube. Mouse explant studies suggest that different thresholds of FGF signaling from the cardiogenic mesoderm induce lung, liver, and pancreas lineages from the ventral foregut progenitor cells. The mechanisms that regulate FGF dose in vivo are unknown. Here we use Xenopus embryos to examine the hypothesis that a prolonged duration of FGF signaling from the mesoderm is required to induce foregut organs.ResultsWe show that both mesoderm and FGF signaling are required for liver and lung development in Xenopus; formally demonstrating that this important step in organ induction is conserved with other vertebrate species. Prolonged contact with the mesoderm and persistent FGF signaling through both MEK and PI3K over an extended period of time are required for liver and lung specification. Inhibition of FGF signaling results in reduced liver and lung development, with a modest expansion of the pancreas/duodenum progenitor domain. Hyper-activation of FGF signaling has the opposite effect expanding liver and lung gene expression and repressing pancreatic markers. We show that FGF signaling is cell autonomously required in the endoderm and that a dominant negative FGF receptor decreases the ability of ventral foregut progenitor cells to contribute to the lung and liver buds.ConclusionsThese results suggest that the liver and lungs are specified at progressively later times in development requiring mesoderm contact for different lengths of time. Our data suggest that this is achieved at least in part through prolonged FGF signaling. In addition to providing a foundation for further mechanistic studies on foregut organogenesis using the experimental advantages of the Xenopus system, these data have implications for the directed differentiation of stem cells into foregut lineages.

FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1

“…FGFs have been shown to be required for the initiation of hepatic development in several divergent species (Jung et al 1999;Chen et al 2003;Zhang et al 2004;Shin et al 2011;Shifley et al 2012). Based on such studies, most protocols used to generate hepatocyte-like cells from hiPSCs include the addition of FGF1 or FGF2, commonly along with BMP4, to induce hepatic specification of the endoderm (Cai et al 2007;Agarwal et al 2008;Hay et al 2008;Basma et al 2009;Song et al 2009;Si-Tayeb et al 2010b;Sullivan et al 2010).…”

“…Subsequent studies have shown that FGF acts in a concentration-dependent manner, with relatively low concentrations inducing hepatic differentiation and higher concentrations inducing lung development (Serls et al 2005). Since the original discovery in mouse embryos, several reports have demonstrated that FGFs play integral roles in regulating hepatic cell fate in evolutionarily distinct species, including Xenopus, chicks, and zebrafish (Jung et al 1999;Chen et al 2003;Zhang et al 2004;Shin et al 2011;Shifley et al 2012).…”

Xenopus as a Model for GI/Pancreas Disease

“…Unique among aquatic model systems, Xenopus embryos rapidly develop lungs in the first few days of embryogenesis, which at the molecular and histological level are similar to early mouse lungs [60••]. Recent studies have revealed that key signaling pathways implicated in mammalian lung development such as Wnt, FGF and BMP, are conserved in Xenopus lung development [60–64]. Using small molecule inhibitors and dominant negative FGFR1 constructs two studies showed that FGF signaling was required for specification of lung tissue, but not thyroid [62, 64].…”

“…Recent studies have revealed that key signaling pathways implicated in mammalian lung development such as Wnt, FGF and BMP, are conserved in Xenopus lung development [60–64]. Using small molecule inhibitors and dominant negative FGFR1 constructs two studies showed that FGF signaling was required for specification of lung tissue, but not thyroid [62, 64]. Shifley et al also showed that both MEK and PI3K pathways downstream of FGF are essential for lung development [64].…”

“…Using small molecule inhibitors and dominant negative FGFR1 constructs two studies showed that FGF signaling was required for specification of lung tissue, but not thyroid [62, 64]. Shifley et al also showed that both MEK and PI3K pathways downstream of FGF are essential for lung development [64]. Using an RA antagonist, RA was also shown to be necessary for lung specification, but only during the early stages [61, 62].…”