Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

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Ranunculus s.l. shows a considerable species diversity and degree of endemism in the Mediterranean region and occurs with various life forms from the lowlands to the highest mountains. Based on a sampling from all continents, sequences of the ITS of nrDNA, the plastid matK, and the adjacent trnK regions were analysed using maximum parsimony and Bayesian inference. Both separate and combined analyses of the two datasets yielded a large core clade of Ranunculus excluding Ficaria, Coptidium, and the extraeuropean genera Beckwithia, Callianthemoides, Halerpestes, and Peltocalathos. The Ceratocephala‐Myosurus‐clade is sister to the core Ranunculus in the plastid and the combined datasets on very long branches, thus supporting a classification of Ceratocephala and Myosurus as separate genera. Within Ranunculus s.s., eight well supported and highly consistent clades correspond either to widespread ecological groups (wetlands, high altitudes/latitudes) or to regional (mainly European) geographical groups. Alpine Mediterranean buttercups belong to orophytic clades, most species of which also occur in the European alpine system; others show widespread northern hemisphere distributions. Only one Mediterranean clade is restricted to the Iberian Peninsula and adjacent regions. Present distribution patterns and molecular data support a hypothesis of an origin of alpine buttercups from lowland ancestors of the same geographical region. At lower altitudes, the predominant life forms, i.e., therophytes and geophytes, evolved multiple times suggesting parallel adaptations to the Mediterranean climate. Geophytes differentiated into an eastern and western Mediterranean group, and are most closely related to the subalpine, non‐monophyletic “R. montanus” group, thus supporting a hypothesis of a common lowland ancestor. Tentative estimates for divergence times of the major clades in Ranunculus s.l. were made based on an age calibration for the Ranunculus‐Xanthorhiza‐split, using matK sequences and penalized likelihood analyses. The results from this study suggest that the split of allied genera from Ranunculus s.s. occurred during the Eocene and Oligocene, with the core clade of Ranunculus being c. 24.0 Myr old. Diversification of Ranunculus s.s. into main ecological/geographical clades took place in the late Miocene, and speciation within the Mediterranean groups during the Pliocene and Pleistocene. Diversification of life forms at lower altitudes occurred mainly during or after the establishment of the Mediterranean climate. Island endemics of Macaronesia and Crete are probably rather young descendents of neighbouring geographical groups. Diversification of alpine groups took place at different geological times, but is in general correlated with periods of colder climate. The high diversity of buttercups is likely a consequence of the broad spectrum of different habitats in the Mediterranean region.

Fibroblast growth factor (FGF) signaling controls axis formation during endoderm development. Studies in lower vertebrates have demonstrated that FGF2 primarily patterns the ventral foregut endoderm into liver and lung, whereas FGF4 exhibits broad anterior-posterior and leftright patterning activities. Furthermore, an inductive role of FGF2 during dorsal pancreas formation has been shown. However, whether FGF2 plays a similar role during human endoderm development remains unknown. Here, we show that FGF2 specifies hESC-derived definitive endoderm (DE) into different foregut lineages in a dosage-dependent manner. Specifically, increasing concentrations of FGF2 inhibits hepatocyte differentiation, whereas intermediate concentration of FGF2 promotes differentiation toward a pancreatic cell fate. At high FGF2 levels specification of midgut endoderm into small intestinal progenitors is increased at the expense of PDX1 1 pancreatic progenitors. High FGF2 concentrations also promote differentiation toward an anterior foregut pulmonary cell fate. Finally, by dissecting the FGF receptor intracellular pathway that regulates pancreas specification, we demonstrate for the first time to the best of our knowledge that induction of PDX1 1 pancreatic progenitors relies on FGF2-mediated activation of the MAPK signaling pathway. Altogether, these observations suggest a broader gut endodermal patterning activity of FGF2 that corresponds to what has previously been advocated for FGF4, implying a functional switch from FGF4 to FGF2 during evolution. Thus, our results provide new knowledge of how cell fate specification of human DE is controlledfacts that will be of great value for future regenerative cell therapies. STEM CELLS 2010;28:45-56 Disclosure of potential conflicts of interest is found at the end of this article.

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