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WIREs Dev Biol
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Notch signaling in the pancreas: patterning and cell fate specification

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Abstract Notch signaling is an evolutionarily conserved mechanism adapted to control binary fate decisions. The first evidence of Notch in pancreatic development focused on its critical role in controlling endocrine fate decisions. Since then, we have come to understand that this signaling system operates iteratively in the pancreas, and is not limited to the control of endocrine fate decision. Notch appears to play a role in early organ development, then during organ domain patterning, and only during a final refinement process, in the control of terminal cell fates. In so doing, Notch receptors and their ligands are under the influence of a wealth of genetic components that together help orchestrate the building of a complex, glandular organ. WIREs Dev Biol 2012, 2:531–544. doi: 10.1002/wdev.99 This article is categorized under: Establishment of Spatial and Temporal Patterns > Repeating Patterns and Lateral Inhibition

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Specification of endocrine cells within pro‐endocrine/duct bipotential trunk progenitor cells (TrPC). (a) Cells within the trunk are active in Notch signaling and Sox9+. Downregulation of Notch allows for Sox9 to activate Ngn3 expression, likely through loss of Notch‐driven Hes1 repression of the Ngn3 gene. Subsequently, Ngn3 will lead to the suppression of Sox9 expression hereby leading to terminal specification of endocrine cell fate. (b) Specification of Ngn3 cells within the TrPC involves Notch‐mediated lateral inhibition. At the secondary transition stage, Ptf1a interacts with Rbp‐j‐like instead of Rbp‐jk and hereby controls maturation of acinar fate. (c) Notch signaling maintains a pool of progenitor cells at different developmental stages from which Ngn3+ cells are specified in part through lateral inhibition. Ngn3+ cells generated at different developmental stages delaminate and differentiate into specific subsets of endocrine cell types which aggregate to form pancreatic islets.

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Segregation of multipotent pancreatic progenitor cells (MPCs) into ‘tip’ and ‘trunk’ progenitor domains. (a) Between the primary and secondary transitions, the pancreatic epithelium undergoes patterning and branching morphogenesis resulting in tip and trunk progenitor domains that are molecularly distinct. (b) Active Notch signaling within trunk progenitor cells (TrPCs) activates expression of the TrPC gene Nkx6.1, which leads to suppression of the TipPC‐specific gene, Ptf1a. Within TipPC cells, Ptf1a suppresses Nkx6.1 expression. As Ptf1a can induce expression of delta (Dll1) at the primary transition stage, it is possible that Ptf1a activates high levels of Dll1 within tip cells resulting in cis‐inhibition of Notch within the TipPC population.

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Notch signaling during multipotent pancreatic progenitor cell (MPC) maintenance and endocrine differentiation at the primary transition. (a) The pancreatic primordium (dorsal bud depicted) at the primary transition stage consists predominantly of proliferative MPCs that are active in Notch. (b) Notch‐mediated progenitor maintenance at the primary transition stage involves Ptf1a. At this stage, Ptf1a interacts with the Notch effector protein Rbp‐jk in activating Hes1 gene expression. (c) Notch‐mediated lateral inhibition between MPCs and Ngn3+ cells leads to differentiation of early glucagon‐expressing endocrine cells.

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