The Roles of Notch Signaling in Liver Development and Disease

Abstract

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases.

Notch Signaling in Kidney Development, Maintenance, and Disease

“…Research conducted for over a century has contributed to our understanding of the mechanism of Notch regulated gene expression in a context dependent manner (reviewed in [9,10], focusing on mechanism of finer aspects of Notch regulation). Notch signaling has a role in the development of multiple organs including the liver [11,12], brain [13], bone [14], in addition to playing a role in malignancies of multiple organs [15]. Considering that several human kidney diseases have been associated with Notch signaling, including Alagille syndrome, Hadju-Cheney syndrome, congenital anomalies of the kidney and urinary tract (CAKUT), and diabetic nephropathy, here we review the functions of Notch signaling in kidney development and maintenance in order to gain insights into Notch-associated kidney diseases.…”

Does Mechanocrine Signaling by Liver Sinusoidal Endothelial Cells Offer New Opportunities for the Development of Anti-fibrotics?

“…Successful adoption of notch inhibition as a therapeutic strategy for liver fibrosis would therefore require cellular targeting to avoid severe side effects. As mentioned previously (section NOTCH), Notch has diverse functions during liver development, homeostasis and disease (57). In hepatocytes (58) or LSECs (43) Notch signaling can induce HSC activation and promotes fibrosis.…”

Tissue-Engineered Bile Ducts for Disease Modeling and Therapy

“…Notch2 and Jagged1 seem to play an essential role in biliary fate during embryonic development. 81,82 Jagged1 ( JAG1), expressed on the nascent portal mesenchyme, stimulates the transdifferentiation of Notch2 expressing hepatoblasts into a biliary phenotype. Upon JAG1/Notch2 interaction, the hairy and enhancer of split-1 (HES1) genes are transcribed subsequently, activating the cholangiocyte-specific TFs HNF1b and SOX9 (sex determining region Y [SRY]-box 9), resulting in development of the ductal plate.…”