Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from \u3b2-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on \u3b2-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations

Erratum to "Evolutionary conserved role of ptf1a in the specification of exocrine pancreatic fates" [Dev. Biol. 268 (2004) 174–184]

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Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements

Glypican (GPC)-3 inhibits cell proliferation and regulates cell survival during development. This action is demonstrated by GPC3 loss-of-function mutations in humans and mice. Here, we show that the GPC3 core protein is processed by a furinlike convertase. This processing is essential for GPC3 modulating Wnt signaling and cell survival in vitro and for supporting embryonic cell movements in zebrafish. The processed GPC3 core protein is necessary and sufficient for the cell-specific induction of apoptosis, but in vitro effects on canonical and noncanonical Wnt signaling additionally require substitution of the core protein with heparan sulfate. Wnt 5A physically associates only with processed GPC3, and only a form of GPC3 that can be processed by a convertase is able to rescue epiboly and convergence/extension movements in GPC3 morphant embryos. Our data imply that the Simpson–Golabi–Behmel syndrome may in part result from a loss of GPC3 controls on Wnt signaling, and suggest that this function requires the cooperation of both the protein and the heparan sulfate moieties of the proteoglycan

Dual-initiation promoters with intertwined canonical and TCT/TOP transcription start sites diversify transcript processing

Variations in transcription start site (TSS) selection reflect diversity of preinitiation complexes and can impact on post-transcriptional RNA fates. Most metazoan polymerase II-transcribed genes carry canonical initiation with pyrimidine/purine (YR) dinucleotide, while translation machinery-associated genes carry polypyrimidine initiator (5’-TOP or TCT). By addressing the developmental regulation of TSS selection in zebrafish we uncovered a class of dual-initiation promoters in thousands of genes, including snoRNA host genes. 5’-TOP/TCT initiation is intertwined with canonical initiation and used divergently in hundreds of dual-initiation promoters during maternal to zygotic transition. Dual-initiation in snoRNA host genes selectively generates host and snoRNA with often different spatio-temporal expression. Dual-initiation promoters are pervasive in human and fruit fly, reflecting evolutionary conservation. We propose that dual-initiation on shared promoters represents a composite promoter architecture, which can function both coordinately and divergently to diversify RNAs

Rethinking the Attractiveness of EU Labour Immigration Policies: Comparative perspectives on the EU, the US, Canada and beyond

Is Europe's immigration policy attractive? One of the priorities driving current EU debates on labour immigration policies is the perceived need to boost Europe's attractiveness vis-á-vis 'talented' and 'highly skilled' immigrants. The EU sees itself playing a role in persuading immigrants to choose Europe over other competing destinations, such as the US or Canada. This book critically examines the determinants and challenges characterising discussions focused on the attractiveness of labour migration policies in the EU as well as other international settings. It calls for re-thinking some of the most commonly held premises and assumptions underlying the narratives of ‘attractiveness’ and ‘global competition for talent’ in migration policy debates. How can an immigration policy, in fact, be made to be ‘attractive’ and what are the incentives at play (if any)? A multidisciplinary team of leading scholars and experts in migration studies address the main issues and challenges related to the role played by rights and discrimination, qualifications and skills, and matching demand and supply in needs-based migration policies. The experiences in other jurisdictions such as South America, Canada and the United States are also covered: Are these countries indeed so ‘attractive’ and ‘competitive’, and if so what makes them more attractive than the EU? On the basis of the discussions and findings presented across the various contributions, the book identifies a number of priorities for policy formulation and design in the next generation of EU labour migration policies. In particular, it highlights important initiatives that the new European Commission should focus on in the years to come

Calsenilin is required for endocrine pancreas development in zebrafish.

peer reviewedCalsenilin/DREAM/Kchip3 is a neuronal calcium-binding protein. It is a multifunctional protein, mainly expressed in neural tissues and implicated in regulation of presenilin processing, repression of transcription, and modulation of A-type potassium channels. Here, we performed a search for new genes expressed during pancreatic development and have studied the spatiotemporal expression pattern and possible role of calsenilin in pancreatic development in zebrafish. We detected calsenilin transcripts in the pancreas from 21 somites to 39 hours postfertilization stages. Using double in situ hybridization, we found that the calsenilin gene was expressed in pancreatic endocrine cells. Loss-of-function experiments with anti-calsenilin morpholinos demonstrated that injected morphants have a significant decrease in the number of pancreatic endocrine cells. Furthermore, the knockdown of calsenilin leads to perturbation in islet morphogenesis, suggesting that calsenilin is required for early islet cell migration. Taken together, our results show that zebrafish calsenilin is involved in endocrine cell differentiation and morphogenesis within the pancreas

Negative cell cycle regulation by Calcineurin is necessary for proper beta cell regeneration in zebrafish

peer reviewedStimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin as a new potential modulator of beta cell regeneration. We showed that calcineurin overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, calcineurin inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. Calcineurin appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal calcineurin as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration

Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics.

Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) inverse-agonist BMS493 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes in zebrafish, including hox genes as well as several pancreatic regulators like mnx1, insm1b, hnf1ba and gata6. Comparison of zebrafish and murine RAR ChIP-seq data highlighted the conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the HoxB locus and driving expression in the nervous system and in the gut in a RA-dependent manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment

La intervención personal de Dios en la historia de israel. El «yo» de Yahvéh en el libro de Amós

1. EN LOS ORÁCULOS CONTRA ISRAEL Y LOS PUEBLOS VECINOS (AM 1-2). a) La decisión de Yahvéh de castigar a Israel y a los pueblos vecinos por sus rebeldías, es irrevocable. b) La destrucción por un fuego. c) Además del fuego,Yahvéh castigará también de otra manera a los culpables. d) Intervenciones de Yahvéh en el pasado a favor de Israel. 2. EN LAS AMONESTACIONES Y AMENAZAS A ISRAEL (AM 3-6). a) Las tradiciones constitutivas de Israel como pueblo. b) Las ocasiones no aprovechadas (Am 4, 6-12). c) La crítica del culto de Israel (Am 5, 21-27). d) El juramento de Yahvéh. e) Los anuncios del castigo inminente. 3. EN LAS VISIONES DE AMÓS (AM 7, 1 - 9, 1-10). a) En el texto mismo de las cinco visiones. b) En el otro material oracular de esta parte. 4. EN LOS ORÁCULOS DE RESTAURACIÓN (AM 9, 11-15). CONCLUSIÓN