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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).
The role of microRNA in neuronal inflammation and survival in the post ischemic brain: a review
Published in Neurological Research, 2023
William A. Li, Aslan Efendizade, Yuchuan Ding
Although miR-124 is elevated in the ischemic region as a result of a stroke, miR-124 levels are decreased in the sub-ventricular zone (SVZ) neuronal progenitor cells [75]. Liu et al. also showed that the down-regulation of miR-124a by ischemic stroke enhances subventricular zone neuronal progenitor cell proliferation, while overexpressing miR-124 attenuates stroke-induced increase in proliferation, indicating that miR-124a in SVZ neural progenitor cells could mediate stroke-induced neurogenesis [75]. Furthermore, the study demonstrated that transfection of neural progenitor cells from the subventricular zone of adult rats with miR-124a repressed Jagged-1 (JAG1) [76]. This reduction in JAG1 mRNA transcript and protein levels leads to inactivation of Notch signaling. The Notch pathway mediates stroke-induced neurogenesis. Activation of Notch signals by stroke increases proliferation of neural progenitor cells, while down-regulation of the Notch signals promotes neural progenitor cell differentiation into neuroblasts. Overexpressing miR-124a in neuronal progenitor cells significantly reduced proliferation and promoted neuronal differentiation after ischemic stroke both in vivo and in vitro models [36].
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].
An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy
Published in OncoImmunology, 2021
Marie Bernardo, Tatiana Tolstykh, Yu-an Zhang, Dinesh S. Bangari, Hui Cao, Kerstin A. Heyl, Joon Sang Lee, Natalia V. Malkova, Katie Malley, Eladio Marquez, Jack Pollard, Hui Qu, Errin Roberts, Sue Ryan, Kuldeep Singh, Fangxian Sun, Emma Wang, Keith Bahjat, Dmitri Wiederschain, Timothy R. Wagenaar
Tumor intrinsic activation of oncogenic signaling pathways has been associated with lack of tumor immune infiltration.8,28 We hypothesized that activation of TGFβ and Notch signaling observed by pathway analysis could be associated with reduced immune infiltration and sought to further characterize TGFβ and Notch activity in MC38-resistant tumors. Dysregulated genes in the TGFβ and Notch pathways included ligands such as TGFB2 and JAG1 and the receptor NOTCH1 (Figure 4a). We next examined whether TGFβ proteins were also upregulated as suggested by mRNA expression. Strikingly, total TGFβ2 was upregulated more than 10-fold in protein lysates from MC38-resistant compared to parental MC38 tumors (Figure 4b). TGFβ3 was upregulated 3-fold, while TGFβ1 was unchanged (Supplemental Figure 5a). As gene expression analysis also revealed upregulation of JAG1 and NOTCH1, we investigated whether these were upregulated at the protein level. Flow cytometry of cultured cells showed increased Jagged1 surface expression in MC38-resistant cells (Supplemental Figure 5b). Activation of the membrane-associated Notch1 receptor triggers a series of cleavage events that results in the release of the intracellular domain, which translocates to the nucleus and activates gene transcription.29 Resistant tumors exhibited increased abundance of cleaved Notch1, consistent with elevated signaling activity (Figure 4b, Supplemental Figure 5c). Altogether, these results confirm activation of TGFβ and Notch pathways in MC38-resistant tumors.