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3. Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea.

Author

de Haan, Sandra, Corbat, Agustin A., Cederroth, Christopher R., Autrum, Lisa G., Hankeova, Simona, Driver, Elizabeth C., Canlon, Barbara, Kelley, Matthew W., and Andersson, Emma R.

Subjects
CORTI'S organ, HAIR cells, CELL differentiation, CELL determination, INNER ear
Abstract

Notch signaling patterns the cochlear organ of Corti, and individuals with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss. We investigated the function of Jag1 in cochlear patterning and signaling using Jag1Ndr/Ndr mice, which are a model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types further revealed that Jag1 represses Notch activation in lateral supporting cells and demonstrated a function for Jag1 in gene regulation and development of outer hair cells. Surprisingly, ectopic 'outer hair cell-like' cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr cochleae, yet they exhibited location-dependent expression of the inner hair cell fate-determinant Tbx2, suggesting Jag1 is required for Tbx2 to drive inner hair cell commitment. This study thus identifies new roles for Jag1 in supporting cells, and in outer hair cell specification and positioning. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Sex differences and risk factors for bleeding in Alagille syndrome

Author

Hankeova, Simona, Van Hul, Noemi, Laznovsky, Jakub, Verboven, Elisabeth, Mangold, Katrin, Hensens, Naomi, Adori, Csaba, Verhoef, Elvira, Zikmund, Tomas, Dawit, Feven, Kavkova, Michaela, Salplachta, Jakub, Sjöqvist, Marika, Johansson, Bengt R, Hassan, Mohamed G, Fredriksson, Linda, Baumgärtel, Karsten, Bryja, Vitezslav, Lendahl, Urban, Jheon, Andrew, Alten, Florian, Fahnehjelm, Kristina Teär, Fischler, Björn, Kaiser, Jozef, and Andersson, Emma R

Published
2022
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5. Author Reply to Peer Reviews of Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial compartment of the developing cochlea

Author

de Haan, Sandra, primary, Corbat, Agustin A, additional, Cederroth, Christopher R, additional, Autrum, Lisa G, additional, Hankeova, Simona, additional, Driver, Elizabeth C, additional, Canlon, Barbara, additional, Kelley, Matthew W, additional, and Andersson, Emma, additional

Published
2024
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7. Front Cover

Author

Iqbal, Afshan, primary, Van Hul, Noemi, additional, Belicova, Lenka, additional, Corbat, Agustin A., additional, Hankeova, Simona, additional, and Andersson, Emma R., additional

Published
2024
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9. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

Author

Andersson, Emma R., Chivukula, Indira V., Hankeova, Simona, Sjöqvist, Marika, Tsoi, Yat Long, Ramsköld, Daniel, Masek, Jan, Elmansuri, Aiman, Hoogendoorn, Anita, Vazquez, Elenae, Storvall, Helena, Netušilová, Julie, Huch, Meritxell, Fischler, Björn, Ellis, Ewa, Contreras, Adriana, Nemeth, Antal, Chien, Kenneth C., Clevers, Hans, Sandberg, Rickard, Bryja, Vitezslav, and Lendahl, Urban

Published
2018
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10. Spatially segregated defects and IGF1-responsiveness of hilar and peripheral biliary organoids from a model of Alagille syndrome.

Author

Iqbal, Afshan, Van Hul, Noemi, Belicova, Lenka, Corbat, Agustin A., Hankeova, Simona, and Andersson, Emma R.

Subjects
INTRAHEPATIC bile ducts, ORGANOIDS, BILE ducts, RNA sequencing, TRANSCRIPTOMES, BIOACTIVE glasses
Abstract

Background & Aims: Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1Ndr/Ndr mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region-specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in Jag1Ndr/Ndr mice, can improve biliary outcomes. Methods: Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult Jag1+/+ and Jag1Ndr/Ndr livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated in vivo by immunostaining. Results: Cell growth assays and transcriptomics demonstrated that Jag1Ndr/Ndr ICOs were less proliferative than Jag1+/+ ICOs. IGF1 specifically rescued survival and growth of Jag1Ndr/Ndr pICOs. Jag1Ndr/Ndr hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake/transport pathways. In vitro ( Jag1Ndr/Ndr hICOs) and in vivo ( Jag1Ndr/Ndr hilar portal tracts) analyses revealed ectopic HNF4a+ hepatocytes. Conclusions: Hilar and peripheral Jag1Ndr/Ndr ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte- to-hepatocyte transdifferentiation. While Jag1Ndr/Ndr pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte-like state and/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Immune cell incompetence and hepatocyte differentiation defects explain mild fibrosis in a model of Alagille syndrome

Author

Mašek, Jan, primary, Filipovic, Iva, additional, Hankeova, Simona, additional, He, Jingyan, additional, Van Hul, Noémi K.M., additional, Belicova, Lenka, additional, Frontino, Anna Maria, additional, Jiroušková, Markéta, additional, Oliveira, Daniel, additional, Turetti, Fabio, additional, Cervenka, Igor, additional, Sarnová, Lenka, additional, Verboven, Elisabeth, additional, Brabec, Tomáš, additional, Björkström, Niklas, additional, Gregor, Martin, additional, Dobeš, Jan, additional, and Andersson, Emma, additional

Published
2023
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14. Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

Author

Mašek, Jan, primary, Filipovic, Iva, additional, Hul, Noémi Van, additional, Belicová, Lenka, additional, Jiroušková, Markéta, additional, Oliveira, Daniel V., additional, Frontino, Anna Maria, additional, Hankeova, Simona, additional, He, Jingyan, additional, Turetti, Fabio, additional, Iqbal, Afshan, additional, Červenka, Igor, additional, Sarnová, Lenka, additional, Verboven, Elisabeth, additional, Brabec, Tomáš, additional, Björkström, Niklas K., additional, Gregor, Martin, additional, Dobeš, Jan, additional, and Andersson, Emma R., additional

Published
2022
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15. Discovery of thyrocyte heterogeneity reveals an essential role of Notch signaling in thyroid function and mammalian homeostasis

Author

Mosteiro, Lluc, primary, Thao Nguyen, Thi Thu, additional, Hankeova, Simona, additional, Reichelt, Mike, additional, Vandriel, Shannon M., additional, Lai, Zijuan, additional, Choudhury, Feroza K., additional, Sangaraju, Dewakar, additional, Kamath, Binita M., additional, Scherl, Alexis, additional, Piskol, Robert, additional, and Siebel, Christian W., additional

Published
2022
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17. Bleeding in patients and mice with Alagille syndrome: sex differences and risk factors

Author

Hankeova, Simona, primary, Van Hul, Noemi, additional, Laznovsky, Jakub, additional, Hensen, Naomi, additional, Verhoef, Elvira, additional, Zikmund, Tomas, additional, Dawit, Feven, additional, Kavkova, Michaela, additional, Salplachta, Jakub, additional, Li, Liting, additional, Sjöqvist, Marika, additional, Johansson, Bengt R., additional, Hassan, Mohamed, additional, Bryja, Vitezslav, additional, Lendahl, Urban, additional, Jheon, Andrew, additional, Wang, Jian She, additional, Alten, Florian, additional, Teär Fahnehjelm, Kristina, additional, Fischler, Björn, additional, Kaiser, Jozef, additional, and Andersson, Emma R., additional

Published
2021
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18. DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome

Author

Hankeova, Simona, primary, Salplachta, Jakub, additional, Zikmund, Tomas, additional, Kavkova, Michaela, additional, Van Hul, Noémi, additional, Brinek, Adam, additional, Smekalova, Veronika, additional, Laznovsky, Jakub, additional, Dawit, Feven, additional, Jaros, Josef, additional, Bryja, Vítězslav, additional, Lendahl, Urban, additional, Ellis, Ewa, additional, Nemeth, Antal, additional, Fischler, Björn, additional, Hannezo, Edouard, additional, Kaiser, Jozef, additional, and Andersson, Emma Rachel, additional

Published
2021
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19. THU-255 - Immune cell incompetence and hepatocyte differentiation defects explain mild fibrosis in a model of Alagille syndrome

Author

Mašek, Jan, Filipovic, Iva, Hankeova, Simona, He, Jingyan, Van Hul, Noémi K.M., Belicova, Lenka, Frontino, Anna Maria, Jiroušková, Markéta, Oliveira, Daniel, Turetti, Fabio, Cervenka, Igor, Sarnová, Lenka, Verboven, Elisabeth, Brabec, Tomáš, Björkström, Niklas, Gregor, Martin, Dobeš, Jan, and Andersson, Emma

Published
2023
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23. Author response: DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome

Author

Hankeova, Simona, primary, Salplachta, Jakub, additional, Zikmund, Tomas, additional, Kavkova, Michaela, additional, Van Hul, Noémi, additional, Brinek, Adam, additional, Smekalova, Veronika, additional, Laznovsky, Jakub, additional, Dawit, Feven, additional, Jaros, Josef, additional, Bryja, Vítězslav, additional, Lendahl, Urban, additional, Ellis, Ewa, additional, Nemeth, Antal, additional, Fischler, Björn, additional, Hannezo, Edouard, additional, Kaiser, Jozef, additional, and Andersson, Emma Rachel, additional

Published
2020
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24. Double resin casting micro computed tomography (CT) reveals biliary and vascular pathology in tandem in a mouse model for alagille syndrome

Author

Hankeova, Simona, primary, Salplachta, Jakub, additional, Zikmund, Tomas, additional, Kavkova, Michaela, additional, Van Hul, Noémi K.M., additional, Brinek, Adam, additional, Smekalova, Veronika, additional, Laznovsky, Jakub, additional, Jaros, Josef, additional, Bryja, Vitezslav, additional, Lendahl, Urban, additional, Ellis, Ewa, additional, Hannezo, Edouard, additional, Kaiser, Jozef, additional, and Andersson, Emma, additional

Published
2020
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26. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

Author

Andersson, Emma R, Chivukula, Indira V, Hankeova, Simona, Sjöqvist, Marika, Tsoi, Yat Long, Ramsköld, Daniel, Masek, Jan, Elmansuri, Aiman, Hoogendoorn, Anita, Vazquez, Elenae, Storvall, Helena, Netušilová, Julie, Huch, Meritxell, Fischler, Björn, Ellis, Ewa, Contreras, Adriana, Nemeth, Antal, Chien, Kenneth C, Clevers, Hans, Sandberg, Rickard, Bryja, Vitezslav, Lendahl, Urban, Huch Ortega, Meritxell [0000-0002-1545-5265], Apollo - University of Cambridge Repository, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Male, Notch, Vertebrae, Mutation, Missense, Mice, Transgenic, Development, Kidney, Transfection, Journal Article, Morphogenesis, Animals, Humans, Genetic Predisposition to Disease, Receptor, Notch2, Mice, Inbred C3H, Gene Expression Profiling, Gene Expression Regulation, Developmental, Heart, Cell Differentiation, Coculture Techniques, Alagille Syndrome, Mice, Inbred C57BL, Organoids, Disease Models, Animal, Bile Ducts, Intrahepatic, HEK293 Cells, Phenotype, Jagged1, Liver, Alagille, Female, Jagged-1 Protein, Signal Transduction
Abstract

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.

Published
2020
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27. DoUble resin casting micro computed tomography (DUCT) reveals biliary and vascular pathology in a mouse model of Alagille syndrome

Author

Hankeova, Simona, primary, Salplachta, Jakub, additional, Zikmund, Tomas, additional, Kavkova, Michaela, additional, Van Hul, Noemi, additional, Brinek, Adam, additional, Smekalova, Veronika, additional, Laznovsky, Jakub, additional, Jaros, Josef, additional, Bryja, Vitezslav, additional, Lendahl, Urban, additional, Ellis, Ewa, additional, Hannezo, Edouard, additional, Kaiser, Jozef, additional, and Andersson, Emma R, additional

Published
2019
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31. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

Author

Andersson, Emma R, Chivukula, Indira V, Hankeova, Simona, Sjöqvist, Marika, Tsoi, Yat Long, Ramsköld, Daniel, Masek, Jan, Elmansuri, Aiman, Hoogendoorn, Anita, Vazquez, Elenae, Storvall, Helena, Netušilová, Julie, Huch, Meritxell, Fischler, Björn, Ellis, Ewa, Contreras, Adriana, Nemeth, Antal, Chien, Kenneth C, Clevers, Hans, Sandberg, Rickard, Bryja, Vitezslav, Lendahl, Urban, Andersson, Emma R, Chivukula, Indira V, Hankeova, Simona, Sjöqvist, Marika, Tsoi, Yat Long, Ramsköld, Daniel, Masek, Jan, Elmansuri, Aiman, Hoogendoorn, Anita, Vazquez, Elenae, Storvall, Helena, Netušilová, Julie, Huch, Meritxell, Fischler, Björn, Ellis, Ewa, Contreras, Adriana, Nemeth, Antal, Chien, Kenneth C, Clevers, Hans, Sandberg, Rickard, Bryja, Vitezslav, and Lendahl, Urban

Abstract

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms.METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines.RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expr

Published
2017

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