The developmental origins of Notch-driven intrahepatic bile duct disorders

Abstract

The Notch signaling pathway is an evolutionarily conserved mechanism of cell–cell communication that mediates cellular proliferation, cell fate specification, and maintenance of stem and progenitor cell populations. In the vertebrate liver, an absence of Notch signaling results in failure to form bile ducts, a complex tubular network that radiates throughout the liver, which, in healthy individuals, transports bile from the liver into the bowel. Loss of a functional biliary network through congenital malformations during development results in cholestasis and necessitates liver transplantation. Here, we examine to what extent Notch signaling is necessary throughout embryonic life to initiate the proliferation and specification of biliary cells and concentrate on the animal and human models that have been used to define how perturbations in this signaling pathway result in developmental liver disorders.

Progression of Notch signaling regulation of B cells under radiation exposure

“…The TAD is capable of autonomous transcriptional activity and directly binds to the coactivators PCAF and GNC5 (64,76). Upon binding of the Notch receptor and ligand, the Notch receptor is cleaved by ADAM family proteins at site 2 (S2), followed by the cleavage of site 3 (S3) by g-secretase (77), which ultimately releases the Notch intracellular domain (NICD), making the NICD readily localized to the nucleus, where it binds to the coactivator (Mastermind-like-1, MAML1) and the transcriptional repressor, RBP-Jk, to promote the activation of target gene expression such as Hes, Hey and Dtx gene families (78)(79)(80).…”

“…Thus, FoB tends to be more genetically diverse than MZB in terms of IgV(D) genes (93). FoB interacts with T helper (Th) cells to form germinal centers, undergo classswitch recombination (CSR) and somatic hypermutation (SHM), and ultimately produce high-affinity antibodies or memory B cells (62,77). Moreover, Notch2 is important for the development of T2 B cells into MZB (93).…”

NOTCH signalling – a core regulator of bile duct disease?

“…Studies demonstrating the centrality of NOTCH signalling in bile duct development and in patterning of the vertebrate biliary system have been reviewed previously ( Martinez Lyons and Boulter, 2021 ). What remains poorly understood is how this essential signal orchestrates bile duct pathophysiology and pathogenesis in postnatal life.…”

“…In this Review, we focus on NOTCH signalling as a paradigm of reiteratively used signals that are critical for normal bile duct development (this has been extensively reviewed elsewhere; Martinez Lyons and Boulter, 2021 ). We then explore how re-expression of NOTCH and its activation is a master regulator of biliary biology in the context of adult biliary disease and cancer.…”