Abstract
The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion that Notch signaling specifies the endocrine lineage. Here, we review the current knowledge of the Notch signaling pathway in pancreatic development and its crosstalk with the Wingless and INT-1 (Wnt) and fibroblast growth factor (FGF) pathways.
Highlights
IntroductionNotch signaling is an evolutionarily conserved pathway for cell-cell communication and cell-fate determination during embryonic development and tissue homeostasis [1,2]; it includes canonical and non-canonical pathways
Notch signaling is an evolutionarily conserved pathway for cell-cell communication and cell-fate determination during embryonic development and tissue homeostasis [1,2]; it includes canonical and non-canonical pathways. The former is initiated by ligand-receptor interactions between adjacent cells [3,4], which results in the activation of the Hes1 gene by a complex consisting of the Notch intracellular domain (NICD), Rbp-Jκ family of nuclear proteins (Rbp-J, Su(H) (Drosophila), and Lag-1 (Caenorhabditis elegans)), and the Mastermind co-activator
We have found that, during pancreatic progenitor cell differentiation, miR-375 inhibited pancreatic progenitor cell proliferation by targeting the Hippo signaling effector Yap1 [59]. miR-375 plays a role in regulating insulin secretion through targeting the myotrophin (Mtpn) and pyruvate dehydrogenase kinase (Pdk1) genes. miR-19b and miR-18a have been shown to directly act on NeuroD1 and Ptf1a 31 UTR, respectively [60,61]
Summary
Notch signaling is an evolutionarily conserved pathway for cell-cell communication and cell-fate determination during embryonic development and tissue homeostasis [1,2]; it includes canonical and non-canonical pathways. The activation of Notch signaling in pancreatic progenitors prevents their differentiation into the endocrine or exocrine cell lineage [17,18]. In the mouse embryonic pancreas, P21 protein (Cdc42/Rac)-activated kinase 3 (Pak3) acts downstream of Ngn to promote cell cycle exit and cell differentiation by repressing cyclin D1 in Ngn3+ endocrine progenitors [51]. MiR-19b and miR-18a have been shown to directly act on NeuroD1 and Ptf1a 31 UTR, respectively [60,61] These two miRNAs may contribute to the regulation of the differentiation and function of β-cells and acinar cells during pancreatic development. Studies on the transcriptional regulation of the pancreas have been reviewed extensively, and not discussed in detail here
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