Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved.

Diabetes mellitus is a metabolic disorder characterized by dysfunction, loss, or insufficient mass of β cells. The main function of β cells is to produce and secrete insulin, the hormone responsible for the regulation of blood glucose levels. Type 1 diabetes (T1D) results from autoimmune destruction of β cells, while type 2 diabetes (T2D) mostly results from β-cell dysfunction or peripheral tissue resistance to insulin, often culminating in β-cell death. Thus, both forms of diabetes can benefit from restoration of β-cell mass. Currently, islet transplantation is the only way to provide new β cells to diabetic patients, but the scarcity of compatible cadaveric donors makes this approach available to only few patients; moreover, it requires lifelong immune suppression

Notch mediated patterning and cell fate allocation of pancreatic progenitor cells

A perturbation calculation is shown to give a satisfactory analytical description of the dc voltage characteristics of a coupled pair of superconducting weak links. In particular it predicts locking intervals over which the individual voltages of the junctions will either be equal or integer multiples of each other. Numerical simulations corroborate the perturbation approach and, as well, reveal the phenomenon of phase slippage between the junctions

Ptf1a triggers GABAergic neuronal cell fates in the retina

International audienceBACKGROUND: In recent years, considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification. However, hitherto studies focused primarily on the six major retinal cell classes (five types of neurons of one type of glial cell), and paid little attention to the specification of different neuronal subtypes within the same cell class. In particular, the molecular machinery governing the specification of the two most abundant neurotransmitter phenotypes in the retina, GABAergic and glutamatergic, is largely unknown. In the spinal cord and cerebellum, the transcription factor Ptf1a is essential for GABAergic neuron production. In the mouse retina, Ptf1a has been shown to be involved in horizontal and most amacrine neurons differentiation. RESULTS: In this study, we examined the distribution of neurotransmitter subtypes following Ptf1a gain and loss of function in the Xenopus retina. We found cell-autonomous dramatic switches between GABAergic and glutamatergic neuron production, concomitant with profound defects in the genesis of amacrine and horizontal cells, which are mainly GABAergic. Therefore, we investigated whether Ptf1a promotes the fate of these two cell types or acts directly as a GABAergic subtype determination factor. In ectodermal explant assays, Ptf1a was found to be a potent inducer of the GABAergic subtype. Moreover, clonal analysis in the retina revealed that Ptf1a overexpression leads to an increased ratio of GABAergic subtypes among the whole amacrine and horizontal cell population, highlighting its instructive capacity to promote this specific subtype of inhibitory neurons. Finally, we also found that within bipolar cells, which are typically glutamatergic interneurons, Ptf1a is able to trigger a GABAergic fate. CONCLUSION: Altogether, our results reveal for the first time in the retina a major player in the GABAergic versus glutamatergic cell specification genetic pathway

Pankreasentwicklung in <i>Xenopus laevis</i>

Bisheriges Wissen über Pankreasentwicklung basiert hauptsächlich auf Studien an Mäusen, als Modelorganismus für Genexpressionsanalysen. Im Rahmen dieser Arbeit wurde Xenopus laevis neu als Modelsystem für Pankreasentwicklung etabliert und die Entstehung dieses Organs auf molekularer Ebene analysiert. Die Identifizierung und Charakterisierung der pankreas-spezifischen Xenopus Protein Disulfid Isomerase (xPDIp) als molekularen Marker für frühe exokrine Pankreasdifferenzierung war hierfür grundlegend. Weiterhin wurden die Rollen der Transkriptionsfaktoren Ptf1a/p48 und XlHbox8, das Xenopus Homolog von Pdx1, in der frühen Pankreasentwicklung untersucht. Die Ergebnisse deuten stark darauf hin, dass eine Zusammenspiel der beiden Transkriptionsfaktoren Ptf1a/p48 und XlHbox8 ausreichend sind, um endodermale Nicht-Pankreaszellen in Pankreasvorläuferzellen zu konvertieren, aus denen sich im folgendem Entwicklungsverlauf exokrines und endokrines Gewebe des Pankreas differenziert

Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved

Editorial summary Recent advances in β-cell regeneration in vivo are providing insights into the mechanisms involved in the conversion of distinct pancreatic cell lineages into β cells. These mechanisms mostly involve reactivation of the gene encoding the pancreatic endocrine cell-specifying transcription factor neurogenin-3

Wnt7b is required for epithelial progenitor growth and operates during epithelial-to-mesenchymal signaling in pancreatic development

AbstractWnt signaling is a well conserved pathway critical for growth, patterning and differentiation of multiple tissues and organs. Previous studies on Wnt signaling in the pancreas have been based predominantly on downstream pathway effector genes such as β-catenin. We here provide evidence that the canonical-pathway member Wnt7b is a physiological regulator of pancreatic progenitor cell growth. Genetic deletion of Wnt7b in the developing pancreas leads to pancreatic hypoplasia due to reduced proliferation of pancreatic progenitor cells during the phase of pancreas development marked by rapid progenitor cell growth. While the differentiation potential of pancreatic progenitor cells is unaffected by Wnt7b deletion, through a gain-of-function analysis, we find that early pancreatic progenitor cells are highly sensitive to Wnt7b expression, but later lose such competence. By modulating the level and the temporal windows of Wnt7b expression we demonstrate a significant impact on organ growth and morphogenesis particularly during the early branching stages of the organ, which negatively affects generation of the pro-endocrine (Ngn3+/Nkx6.1+), and pro-acinar (Ptf1A+) fields. Consequently, Wnt7b gain-of-function results in failed morphogenesis and almost complete abrogation of the differentiation of endocrine and acinar cells, leading to cystic epithelial metaplasia expressing ductal markers including Sox9, Hnf6 and Hnf1β. While Wnt7b is expressed exclusively in the developing pancreatic epithelium, adjacent mesenchymal cells in the organ display a direct trophic response to elevated Wnt7b and increase expression of Lef1, cFos and desmin. Of note, in contrast to the pancreatic epithelium, the pancreatic mesenchyme remains competent to respond to Wnt7b ligand, at later stages in development. We conclude that Wnt7b helps coordinate pancreatic development through autocrine, as well as paracrine mechanisms, and as such represents a novel bi-modal morphogen ligand

Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment

AbstractNgn3 is recognized as a regulator of pancreatic endocrine formation, and Notch signaling as an important negative regulator Ngn3 gene expression. By conditionally controlling expression of Ngn3 in the pancreas, we find that these two signaling components are dynamically linked. This connection involves transcriptional repression as previously shown, but also incorporates a novel post-translational mechanism. In addition to its ability to promote endocrine fate, we provide evidence of a competing ability of Ngn3 in the patterning of multipotent progenitor cells in turn controlling the formation of ducts. On one hand, Ngn3 cell-intrinsically activates endocrine target genes; on the other, Ngn3 cell-extrinsically promotes lateral signaling via the Dll1>Notch>Hes1 pathway which substantially limits its ability to sustain endocrine formation. Prior to endocrine commitment, the Ngn3-mediated activation of the Notch>Hes1 pathway impacts formation of the trunk domain in the pancreas causing multipotent progenitors to lose acinar, while gaining endocrine and ductal, competence. The subsequent selection of fate from such bipotential progenitors is then governed by lateral inhibition, where Notch>Hes1-mediated Ngn3 protein destabilization serves to limit endocrine differentiation by reducing cellular levels of Ngn3. This system thus allows for rapid dynamic changes between opposing bHLH proteins in cells approaching a terminal differentiation event. Inhibition of Notch signaling leads to Ngn3 protein stabilization in the normal mouse pancreas explants. We conclude that the mutually exclusive expression pattern of Ngn3/Hes1 proteins in the mammalian pancreas is partially controlled through Notch-mediated post-translational regulation and we demonstrate that the formation of insulin-producing beta-cells can be significantly enhanced upon induction of a pro-endocrine drive combined with the inhibition of Notch processing