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Alagille Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The JAG1 gene on chromosome 20p12.2 spans over 36 kb consisting of 26 exons, which range from 28 bp to 2284 bp in size, while 25 introns in between vary from 89 bp to nearly 9 kb in size. It produces three different transcripts by alternative splicing, with the most important one being 5.901 kb in size, which encodes a 1218 aa cell surface protein (JAG1). Structurally, JAG1 comprises a relatively small intracellular domain, a transmembrane domain, and a larger extracellular component. In turn, the extracellular component consists of a 21 aa signal peptide, an N-terminal region, a 40 aa highly conserved DSL domain (named for the Drosophila melanogaster and Caenorhabditis elegans ligands, delta, serrate, and lag-2), 16 epidermal growth factor(EGF)-like repeats, and a cysteine-rich region [4].
Microdeletion Syndromes
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Gopalrao V. N. Velagaleti, Nancy J. Carpenter
On the basis of several published reports showing cytogenetically visible deletions (Fig. 2) or translocations involving the short arm of chromosome 20, AGS was mapped to 20p12 (12). A cell surface protein that functions as a key signaling molecule called Jagged 1 (JAG1) was identified by two groups to be physically located within this region, commonly deleted on chromosome 20p. Mutations in JAG1 were found in AGS patients in multiple families and thus confirming that JAG1 is the AGS disease gene (13,14).
3D bioprinting for organ and organoid models and disease modeling
Published in Expert Opinion on Drug Discovery, 2023
Amanda C. Juraski, Sonali Sharma, Sydney Sparanese, Victor A. da Silva, Julie Wong, Zachary Laksman, Ryan Flannigan, Leili Rohani, Stephanie M. Willerth
One example showcasing the potential of liver organoids in disease modeling and regenerative medicine is demonstrated by Guan et al [30]. This study highlights the utility of liver organoids by modeling Alagille syndrome (ALGS), a defect caused by disturbed NOTCH signaling. The study aimed to understand the mechanism and cell types involved in the disease. ALGS patient-induced pluripotent stem cells (iPSCs) were used to generate hepatobiliary organoids (HOs) and compared to control using CRISPR-engineered lines. The results revealed that patient organoids lacked duct structures, exhibited reduced cholangiocyte marker expression, and displayed decreased Jagged 1 (JAG1) expression during HO development. JAG1 is a notch ligand, and its mutations result in ALGS and impaired bile duct formation. The ALGS HOs were unable to form secondary organoids, indicating an impaired regenerative capacity, and demonstrating that genome engineering can be used to generate and repair disease lines [31].
Blockade of the Notch1/Jagged1 pathway in Kupffer cells aggravates ischemia-reperfusion injury of orthotopic liver transplantation in mice
Published in Autoimmunity, 2019
He Bai, Jian Wen, Jian-Ping Gong, Hao Wu, Fang-Chao Yuan, Ding Cao, Ya-Kun Wu, Xing Lai, Meng-Hao Wang
Notch pathway is essential in macrophage function. Notch plays a vital role in multiple stages of multiple cell types, including immune cells [8,9]. Notch proteins in the mammalian family includes four receptors (Notch1–4) and a set of ligands comprising of Jagged (Jag1 and 2) and Delta-like members (DLL1, 3, and 4). Notch receptors and ligands are the extracellular domains required for transmembrane proteins and extracellular domains, which are the result of close ligand receptor interactions [10]. This intercellular interaction results in a cleavage sequence of the receptor, mediated by a protease such as a protease, which results in the release of the Notch intracellular domain (NICD) into the nucleus [10], and can induce activation and division of the target gene Hairy and enhancer of split-1 (Hes1), which play an important role in regulating downstream inflammatory factors. These effects are consistent with the Notch1/Jagged1 pathway [11,12]. Myeloid-specific Notch1 deficiency augmented macrophage activation and hepatocellular damage in a mouse warm IRI model [13].
The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation
Published in Critical Reviews in Toxicology, 2018
Experiments by Thatcher et al. (2016) indicated that endogenous AHR ligands might be involved in the physiological regulation of Th2-mediated immunity in the lung via a dendritic cell-dependent mechanism. They found that after murine pulmonary dendritic cells were incubated overnight with LPS and OVA, addition of 100 or 200 nM FICZ markedly inhibited the proliferation of T cells (Thatcher et al. 2016). FICZ was also suggested to exert anti-asthmatic effects on the basis of the observation that when injected i.p. to a murine model of allergic asthma during sensitization to OVA, 3 or 30 μg of FICZ kg−1 reduced pulmonary eosinophilia and expression of Th2 cytokines (Jeong et al. 2012) (Table 1). In another examination of allergic asthma in mice, 30 nM FICZ activated Jagged 1 (Jag1), a component of the pro-inflammatory Notch pathway, in BMDCs (Xia et al. 2015).