Understanding the molecular mechanisms that promote successful tissue regeneration is critical for continued advancements in regenerative medicine. Vertebrate amphibian tadpoles of the species Xenopus laevis and Xenopus tropicalis have remarkable abilities to regenerate their tails following amputation 1, 2, via the coordinated activity of numerous growth factor signaling pathways, including the Wnt, Fgf, BMP, notch, and TGFβ pathways 3-6. Little is known, however, about the events that act upstream of these signalling pathways following injury. Here, we show that Xenopus tadpole tail amputation induces a sustained production of reactive oxygen species (ROS) during tail regeneration. Lowering ROS levels, via pharmacological or genetic approaches, reduces cell proliferation and impairs tail regeneration. Genetic rescue experiments restored both ROS production and the initiation of the regenerative response. Sustained increased ROS levels are required for Wnt/β-catenin signaling and the activation of one of its major downstream targets, fgf20 7, which, in turn, is essential for proper tail regeneration. These findings demonstrate that injury-induced ROS production is an important regulator of tissue regeneration.

The c-Abl tyrosine kinase is inhibited by mechanisms that are poorly understood. Disruption of these mechanisms in the Bcr-Abl oncoprotein leads to several forms of human leukemia. We found that like Src kinases, c-Abl 1b is activated by phosphotyrosine ligands. Ligand-activated c-Abl is particularly sensitive to the anti-cancer drug STI-571/Gleevec/imatinib (STI-571). The SH2 domain-phosphorylated tail interaction in Src kinases is functionally replaced in c-Abl by an intramolecular engagement of the N-terminal myristoyl modification with the kinase domain. Functional studies coupled with structural analysis define a myristoyl/phosphotyrosine switch in c-Abl that regulates docking and accessibility of the SH2 domain. This mechanism offers an explanation for the observed cellular activation of c-Abl by tyrosine-phosphorylated proteins, the intracellular mobility of c-Abl, and it provides new insights into the mechanism of action of STI-571.

SummaryFibroblast growth factor (FGF) signalling has been implicated during several phases of early embryogenesis, including the patterning of the embryonic axes, the induction and/or maintenance of several cell lineages and the coordination of morphogenetic movements. Here, we summarise our current understanding of the regulation and roles of FGF signalling during early vertebrate development. Key words: Fibroblast growth factor, Embryogenesis, Mesoderm, Morphogenesis, Patterning, Stem cells IntroductionThe first fibroblast growth factor (FGF) ligands, FGF1 and FGF2, were initially purified from brain as mitogenic factors of fibroblasts grown in culture (Gospodarowicz and Moran, 1975). Since their discovery, FGF ligands and their receptors have been implicated in numerous biological processes (Table 1), and their dysregulation causes several congenital diseases (such as dwarfism) and some types of cancer (Table 2) (reviewed by Beenken and Mohammadi, 2009). In addition to their mitogenic capacity, FGFs can also modulate cell survival, migration and differentiation in culture (Dailey et al., 2005;Xian et al., 2005).During embryogenesis, FGF signalling plays an important role in the induction/maintenance of mesoderm and neuroectoderm, the control of morphogenetic movements, anteroposterior (AP) patterning, somitogenesis and the development of various organs (Table 1) (Bottcher and Niehrs, 2005; Itoh, 2007;McIntosh et al., 2000). Here, we briefly describe the FGF signalling pathway and then summarise the main developmental processes in which FGF signalling plays an important role during early vertebrate embryogenesis, including cell fate specification and axis determination. FGF signalling: an overviewMembers of the FGF family of extracellular ligands are characterised by a conserved core of 140 amino acids and their strong affinity for heparin sulphate (HS) (see Glossary, Box 1). In vertebrates, 22 family members have been identified and are grouped into seven subfamilies according to their sequence homology and function (Ornitz, 2000). All FGFs, with the exception of the intracellular FGFs (iFGFs,, signal through a family of tyrosine kinase receptors, the FGF receptors (FGFRs). In vertebrates, the FGFR family consists of four genes, FGFR1-4, which undergo alternative splicing in their extracellular domain to generate a vast variety of receptors with different affinities for their ligands (Zhang et al., 2006). FGF ligands bind the extracellular domain of the FGFRs in combination with heparan sulphate to form a 2:2:2 FGF:FGFR:heparan dimer. The dimerisation of the receptor results in the transphosphorylation of specific intracellular tyrosine residues ( Fig. 1). This triggers the activation of cytoplasmic signal transduction pathways, such as the Ras/ERK pathway (which is associated with proliferation and Development 137, 3731-3742 (2010) In vertebrates, the blastopore gives rise to the anus of the embryo. Bottle cells. Cells that lead to the initiation of involution during gastrulation, as they adopt a charact...

Despite years of investigation, the molecular mechanism responsible for regulation of the c-Abl tyrosine kinase has remained elusive. We now report inhibition of the catalytic activity of purified c-Abl in vitro, demonstrating that regulation is an intrinsic property of the molecule. We show that the interaction of the N-terminal 80 residues with the rest of the protein mediates autoregulation. This N-terminal "cap" is required to achieve and maintain inhibition, and its loss turns c-Abl into an oncogenic protein and contributes to deregulation of BCR-Abl.

The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c‐Abl is an important effector of c‐Src for PDGF‐ and serum‐induced DNA synthesis. Inactivation of cytoplasmic c‐Abl by the kinase‐ inactive Abl‐PP‐K− (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase‐inactive SrcK295M induced a G1 block that was overcome by the constitutively active Abl‐PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl‐PP‐K− was not compensated by Src. c‐Src‐induced c‐Abl activation involves phosphorylation of Y245 and Y412, two residues required for c‐Abl mitogenic function. Finally, we found that p53 inactivation and c‐myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c‐Abl: c‐Abl function was dispensable in cells deficient in active p53 and inhibition of c‐Abl reduced mitogen‐induced c‐myc expression. These data identify a novel function of cytoplasmic c‐Abl in the signalling pathways regulating growth factor‐induced c‐myc expression and we propose the existence of a tyro sine kinase signalling cascade (PDGFR/c‐Src/c‐Abl) important for mitogenesis.