10 results on '"Gates KP"'
Search Results
2. Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling.
- Author
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Zhao C, Matalonga J, Lancman JJ, Liu L, Xiao C, Kumar S, Gates KP, He J, Graves A, Huisken J, Azuma M, Lu Z, Chen C, Ding BS, and Dong PDS
- Subjects
- Animals, Humans, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Mosaicism, SOX9 Transcription Factor genetics, SOX9 Transcription Factor metabolism, Zebrafish genetics, Zebrafish metabolism, Receptors, Notch genetics, Receptors, Notch metabolism, Regeneration, Fibroblasts, Alagille Syndrome genetics, Alagille Syndrome metabolism, Signal Transduction, Bile Ducts, Intrahepatic cytology, Bile Ducts, Intrahepatic pathology
- Abstract
Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating jag1b and jag2b allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-of-function analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic sox9b expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.
- Published
- 2022
- Full Text
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3. Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome.
- Author
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Zhao C, Lancman JJ, Yang Y, Gates KP, Cao D, Barske L, Matalonga J, Pan X, He J, Graves A, Huisken J, Chen C, and Dong PDS
- Subjects
- Animals, Cell Transdifferentiation, Disease Models, Animal, Humans, Liver growth & development, Liver metabolism, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction, Zebrafish, Alagille Syndrome genetics, Alagille Syndrome metabolism, Bile Ducts, Extrahepatic growth & development, Bile Ducts, Extrahepatic physiology, Bile Ducts, Intrahepatic growth & development, Bile Ducts, Intrahepatic physiology, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Liver Regeneration physiology, Receptors, Notch metabolism, Zebrafish Proteins genetics, Zebrafish Proteins metabolism
- Abstract
Background and Aims: Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene JAGGED1, leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown., Approach and Results: Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch-dependent mechanism. Combining multiple lineage tracing strategies with whole-liver three-dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte-to-IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue-specific mosaic analysis with an inducible dominant-negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids., Conclusions: Our data show that IHD cells regenerate upon resumption of Jagged/Notch signaling, from multipotent progenitors originating from an Fgf-dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced., (© 2021 American Association for the Study of Liver Diseases.)
- Published
- 2022
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4. CoRest1 regulates neurogenesis in a stage-dependent manner.
- Author
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Monestime CM, Taibi A, Gates KP, Jiang K, and Sirotkin HI
- Subjects
- Animals, Co-Repressor Proteins genetics, Co-Repressor Proteins metabolism, Embryo, Nonmammalian, Gastrula physiology, Gene Expression Regulation, Developmental, Mutant Proteins, Nerve Tissue Proteins genetics, Repressor Proteins metabolism, Sin3 Histone Deacetylase and Corepressor Complex metabolism, Zebrafish, Zebrafish Proteins genetics, Co-Repressor Proteins physiology, Nerve Tissue Proteins metabolism, Neurogenesis drug effects, Zebrafish Proteins metabolism
- Abstract
Background: Developmental processes, including neuronal differentiation, require precise regulation of transcription. The RE-1 silencing transcription factor (Rest), is often called a "master neuronal regulator" due to its large number of neural-specific targets. Rest recruits CoRest (Rcor) and Sin3 corepressor complexes to gene regulatory sequences. CoRest not only associates with Rest, but with other transcription regulators. In this study, we generated zebrafish rcor1 mutants using transcription activator-like effector nucleases (TALENS), to study its requisite role in repression of Rest target genes as well as Rest-independent Rcor1 developmental functions., Results: While rcor1 mutants have a slight decrease in fitness, most survived and produced viable offspring. We examined expression levels of RE1-containing genes in maternal zygotic rcor1 (MZrcor1) mutants and found that Rcor1 is generally not required for the repression of Rest target genes at early stages. However, MZrcor1 mutants undergo more rapid neurogenesis compared to controls. We found that at gastrula stages, Rcor1 acts as a repressor of her gene family, but at later stages, her6 decreased in the MZrcor1 mutant., Conclusions: Based on these findings, the central role of CoRest1 in neurogenesis is likely due to a Rest-independent role rather than as a Rest corepressor., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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5. Endoderm Jagged induces liver and pancreas duct lineage in zebrafish.
- Author
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Zhang D, Gates KP, Barske L, Wang G, Lancman JJ, Zeng XI, Groff M, Wang K, Parsons MJ, Crump JG, and Dong PDS
- Subjects
- Alagille Syndrome genetics, Animals, Cell Lineage, Endoderm cytology, Zebrafish, Bile Ducts, Intrahepatic embryology, Calcium-Binding Proteins genetics, Endoderm metabolism, Gene Expression Regulation, Developmental, Jagged-2 Protein genetics, Pancreatic Ducts embryology, Zebrafish Proteins genetics
- Abstract
Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos with compound homozygous mutations in two Notch ligand genes, jagged1b (jag1b) and jagged2b (jag2b) exhibit a complete loss of canonical Notch activity and duct cells within the liver and exocrine pancreas, whereas hepatocyte and acinar pancreas development is not affected. Further, animal chimera studies demonstrate that wild-type endoderm cells within the liver and pancreas can rescue Notch activity and duct lineage specification in adjacent cells lacking jag1b and jag2b expression. We conclude that these two Notch ligands are directly and solely responsible for all duct lineage specification in these organs in zebrafish. Our study uncovers genes required for lineage specification of the intrahepatopancreatic duct cells, challenges the role of duct cells as progenitors, and suggests a genetic mechanism for ALGS ductal paucity.The hepatopancreatic duct cells connect liver hepatocytes and pancreatic acinar cells to the intestine, but the mechanism for their lineage specification is unclear. Here, the authors reveal that Notch ligands Jagged1b and Jagged2b induce duct cell lineage in the liver and pancreas of the zebrafish.
- Published
- 2017
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6. Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes.
- Author
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Hockman D, Burns AJ, Schlosser G, Gates KP, Jevans B, Mongera A, Fisher S, Unlu G, Knapik EW, Kaufman CK, Mosimann C, Zon LI, Lancman JJ, Dong PDS, Lickert H, Tucker AS, and Baker CV
- Subjects
- Animals, Anura, Biological Evolution, Lampreys, Zebrafish, Cell Hypoxia, Cell Lineage, Neuroendocrine Cells, Neuroepithelial Cells
- Abstract
The evolutionary origins of the hypoxia-sensitive cells that trigger amniote respiratory reflexes - carotid body glomus cells, and 'pulmonary neuroendocrine cells' (PNECs) - are obscure. Homology has been proposed between glomus cells, which are neural crest-derived, and the hypoxia-sensitive 'neuroepithelial cells' (NECs) of fish gills, whose embryonic origin is unknown. NECs have also been likened to PNECs, which differentiate in situ within lung airway epithelia. Using genetic lineage-tracing and neural crest-deficient mutants in zebrafish, and physical fate-mapping in frog and lamprey, we find that NECs are not neural crest-derived, but endoderm-derived, like PNECs, whose endodermal origin we confirm. We discover neural crest-derived catecholaminergic cells associated with zebrafish pharyngeal arch blood vessels, and propose a new model for amniote hypoxia-sensitive cell evolution: endoderm-derived NECs were retained as PNECs, while the carotid body evolved via the aggregation of neural crest-derived catecholaminergic (chromaffin) cells already associated with blood vessels in anamniote pharyngeal arches.
- Published
- 2017
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7. Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia.
- Author
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Liu C, Gates KP, Fang L, Amar MJ, Schneider DA, Geng H, Huang W, Kim J, Pattison J, Zhang J, Witztum JL, Remaley AT, Dong PD, and Miller YI
- Subjects
- Aging, Amino Acid Sequence, Animals, Apolipoprotein C-II chemistry, Apolipoprotein C-II genetics, Base Sequence, Blood Vessels drug effects, Blood Vessels metabolism, Diet, Disease Models, Animal, Endonucleases metabolism, Humans, Hyperlipidemias pathology, Injections, Larva, Lipoproteins metabolism, Molecular Sequence Data, Mutation genetics, Neovascularization, Physiologic, Pancreas drug effects, Pancreas growth & development, Pancreas pathology, Peptides pharmacology, Phenotype, Plasma metabolism, Trans-Activators metabolism, Triglycerides metabolism, Zebrafish Proteins chemistry, Zebrafish Proteins genetics, Apolipoprotein C-II deficiency, Hyperlipidemias genetics, Models, Genetic, Zebrafish genetics, Zebrafish Proteins deficiency
- Abstract
Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase. Human patients with APOC2 deficiency display severe hypertriglyceridemia while consuming a normal diet, often manifesting xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease. Animal models to study hypertriglyceridemia are limited, with no Apoc2-knockout mouse reported. To develop a genetic model of hypertriglyceridemia, we generated an apoc2 mutant zebrafish characterized by the loss of Apoc2 function. apoc2 mutants show decreased plasma lipase activity and display chylomicronemia and severe hypertriglyceridemia, which closely resemble the phenotype observed in human patients with APOC2 deficiency. The hypertriglyceridemia in apoc2 mutants is rescued by injection of plasma from wild-type zebrafish or by injection of a human APOC2 mimetic peptide. Consistent with a previous report of a transient apoc2 knockdown, apoc2 mutant larvae have a minor delay in yolk consumption and angiogenesis. Furthermore, apoc2 mutants fed a normal diet accumulate lipid and lipid-laden macrophages in the vasculature, which resemble early events in the development of human atherosclerotic lesions. In addition, apoc2 mutant embryos show ectopic overgrowth of pancreas. Taken together, our data suggest that the apoc2 mutant zebrafish is a robust and versatile animal model to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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8. Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb.
- Author
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Lancman JJ, Zvenigorodsky N, Gates KP, Zhang D, Solomon K, Humphrey RK, Kuo T, Setiawan L, Verkade H, Chi YI, Jhala US, Wright CV, Stainier DY, and Dong PD
- Subjects
- Animals, Animals, Genetically Modified, Cell Differentiation genetics, Cell Differentiation physiology, Hepatocyte Nuclear Factor 1-beta genetics, Signal Transduction genetics, Signal Transduction physiology, Wnt Proteins genetics, Zebrafish, Zebrafish Proteins genetics, Hepatocyte Nuclear Factor 1-beta metabolism, Hepatopancreas cytology, Hepatopancreas metabolism, Stem Cells cytology, Stem Cells metabolism, Wnt Proteins metabolism, Zebrafish Proteins metabolism
- Abstract
Although the liver and ventral pancreas are thought to arise from a common multipotent progenitor pool, it is unclear whether these progenitors of the hepatopancreas system are specified by a common genetic mechanism. Efforts to determine the role of Hnf1b and Wnt signaling in this crucial process have been confounded by a combination of factors, including a narrow time frame for hepatopancreas specification, functional redundancy among Wnt ligands, and pleiotropic defects caused by either severe loss of Wnt signaling or Hnf1b function. Using a novel hypomorphic hnf1ba zebrafish mutant that exhibits pancreas hypoplasia, as observed in HNF1B monogenic diabetes, we show that hnf1ba plays essential roles in regulating β-cell number and pancreas specification, distinct from its function in regulating pancreas size and liver specification, respectively. By combining Hnf1ba partial loss of function with conditional loss of Wnt signaling, we uncover a crucial developmental window when these pathways synergize to specify the entire ventrally derived hepatopancreas progenitor population. Furthermore, our in vivo genetic studies demonstrate that hnf1ba generates a permissive domain for Wnt signaling activity in the foregut endoderm. Collectively, our findings provide a new model for HNF1B function, yield insight into pancreas and β-cell development, and suggest a new mechanism for hepatopancreatic specification.
- Published
- 2013
- Full Text
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9. The transcriptional repressor REST/NRSF modulates hedgehog signaling.
- Author
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Gates KP, Mentzer L, Karlstrom RO, and Sirotkin HI
- Subjects
- Animals, Embryo, Nonmammalian metabolism, Epistasis, Genetic, Hedgehog Proteins genetics, In Situ Hybridization, Models, Biological, Repressor Proteins genetics, Signal Transduction genetics, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Zebrafish embryology, Zebrafish genetics, Zebrafish metabolism, Hedgehog Proteins metabolism, Repressor Proteins metabolism, Transcription Factors metabolism
- Abstract
The spatial and temporal control of gene expression is key to generation of specific cellular fates during development. Studies of the transcriptional repressor REST/NRSF (RE1 Silencing Transcription Factor or Neural Restrictive Silencing Factor) have provided important insight into the role that epigenetic modifications play in differential gene expression. However, the precise function of REST during embryonic development is not well understood. We have discovered a novel interaction between zebrafish Rest and the Hedgehog (Hh) signaling pathway. We observed that Rest knockdown enhances or represses Hh signaling in a context-dependant manner. In wild-type embryos and embryos with elevated Hh signaling, Rest knockdown augments transcription of Hh target genes. Conversely, in contexts where Hh signaling is diminished, Rest knockdown has the opposite effect and Hh target gene expression is further attenuated. Epistatic analysis revealed that Rest interacts with the Hh pathway at a step downstream of Smo. Furthermore, we present evidence implicating the bifunctional, Hh signaling component Gli2a as key to the Rest modulation of the Hh response. The role of Rest as a regulator of Hh signaling has broad implications for many developmental contexts where REST and Hh signaling act., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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10. Expression and regulation of the zinc finger transcription factor Churchill during zebrafish development.
- Author
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Londin ER, Mentzer L, Gates KP, and Sirotkin HI
- Subjects
- Animals, Blastula physiology, Cell Movement genetics, Cell Movement physiology, Chickens genetics, Embryo, Nonmammalian physiology, Female, Fibroblast Growth Factors physiology, Genome, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription, Genetic, Zebrafish embryology, Zebrafish growth & development, Zinc Fingers genetics, Zygote physiology, Gene Expression Regulation, Developmental, Trans-Activators genetics, Zebrafish genetics, Zebrafish Proteins genetics
- Abstract
During gastrulation dynamic cell movements establish the germ layers and shape the body axis of the vertebrate embryo. The zinc finger protein Churchill (chch) has been proposed to be a key regulator of these movements. We examined the expression pattern of chch in zebrafish and studied the regulation of chch by FGF signaling. We observed zygotic expression of chch during early cleavage stages. Two lines of evidence demonstrate that chch is zygotically expressed prior to the mid-blastula transition. First, blocking transcription during early cleavage stages represses chch expression. Second, endogenous levels of chch transcripts increase between 1-cell and 16-cell embryos. chch remains widely expressed during blastula and gastrula stages but scattered cells express higher levels of chch. By somitogenesis, chch is expressed in the ventral-most cells of the embryo adjacent to the yolk. In addition, transcripts are also observed in superficial cells on the surface of the yolk, in presumptive mucous cells and keratinocytes. By 30 hpf transcripts are observed in anterior neural tissue and ventral cells adjacent to the yolk. Over the next three days chch expression is indistinct until 4 dpf when we observe expression in the pharynx and gut. We show that activation of FGF signaling during gastrulation is sufficient to induce chch expression. In addition, we demonstrate that blocking FGF signaling between the 4-cell and shield stages represses chch expression.
- Published
- 2007
- Full Text
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