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Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
(2019) Dev Cell 48: 49-63.e7
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Endocrine Cells, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Transcription Factors
Show Abstract · Added February 6, 2019
In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; when and how the Neurog3 cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3 cells co-expressing Myt1 (i.e., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.
Published by Elsevier Inc.
1 Communities
1 Members
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13 MeSH Terms
ROCK-nmMyoII, Notch and gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche.
Bankaitis ED, Bechard ME, Gu G, Magnuson MA, Wright CVE
(2018) Development 145:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Movement, Endocrine Cells, Gene Dosage, Mice, Mice, Transgenic, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, Stem Cells, Transcriptional Activation, rho-Associated Kinases
Show Abstract · Added August 24, 2018
During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed state, progenitors become endocrine committed via upregulation of We find that the to transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through -expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.
© 2018. Published by The Company of Biologists Ltd.
2 Communities
2 Members
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15 MeSH Terms
Striking parallels between carotid body glomus cell and adrenal chromaffin cell development.
Hockman D, Adameyko I, Kaucka M, Barraud P, Otani T, Hunt A, Hartwig AC, Sock E, Waithe D, Franck MCM, Ernfors P, Ehinger S, Howard MJ, Brown N, Reese J, Baker CVH
(2018) Dev Biol 444 Suppl 1: S308-S324
MeSH Terms: Adrenal Glands, Animals, Basic Helix-Loop-Helix Transcription Factors, Body Patterning, Carotid Body, Cell Differentiation, Cell Hypoxia, Chick Embryo, Chickens, Chromaffin Cells, Mice, Mice, Knockout, Myelin Proteolipid Protein, Neural Crest, Neurons, Pericytes, Transcription Factors
Show Abstract · Added May 30, 2018
Carotid body glomus cells mediate essential reflex responses to arterial blood hypoxia. They are dopaminergic and secrete growth factors that support dopaminergic neurons, making the carotid body a potential source of patient-specific cells for Parkinson's disease therapy. Like adrenal chromaffin cells, which are also hypoxia-sensitive, glomus cells are neural crest-derived and require the transcription factors Ascl1 and Phox2b; otherwise, their development is little understood at the molecular level. Here, analysis in chicken and mouse reveals further striking molecular parallels, though also some differences, between glomus and adrenal chromaffin cell development. Moreover, histology has long suggested that glomus cell precursors are 'émigrés' from neighbouring ganglia/nerves, while multipotent nerve-associated glial cells are now known to make a significant contribution to the adrenal chromaffin cell population in the mouse. We present conditional genetic lineage-tracing data from mice supporting the hypothesis that progenitors expressing the glial marker proteolipid protein 1, presumably located in adjacent ganglia/nerves, also contribute to glomus cells. Finally, we resolve a paradox for the 'émigré' hypothesis in the chicken - where the nearest ganglion to the carotid body is the nodose, in which the satellite glia are neural crest-derived, but the neurons are almost entirely placode-derived - by fate-mapping putative nodose neuronal 'émigrés' to the neural crest.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity.
Löf-Öhlin ZM, Nyeng P, Bechard ME, Hess K, Bankaitis E, Greiner TU, Ameri J, Wright CV, Semb H
(2017) Nat Cell Biol 19: 1313-1325
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Polarity, Epithelial Cells, ErbB Receptors, Insulin-Secreting Cells, Mice, Mice, Knockout, Morphogenesis, Nerve Tissue Proteins, Neuropeptides, Organogenesis, Phosphatidylinositol 3-Kinases, Protein Kinase C, Signal Transduction, rac1 GTP-Binding Protein
Show Abstract · Added November 7, 2017
Apicobasal polarity is known to affect epithelial morphogenesis and cell differentiation, but it remains unknown how these processes are mechanistically orchestrated. We find that ligand-specific EGFR signalling via PI(3)K and Rac1 autonomously modulates apicobasal polarity to enforce the sequential control of morphogenesis and cell differentiation. Initially, EGF controls pancreatic tubulogenesis by negatively regulating apical polarity induction. Subsequently, betacellulin, working via inhibition of atypical protein kinase C (aPKC), causes apical domain constriction within neurogenin3 endocrine progenitors, which results in reduced Notch signalling, increased neurogenin3 expression, and β-cell differentiation. Notably, the ligand-specific EGFR output is not driven at the ligand level, but seems to have evolved in response to stage-specific epithelial influences. The EGFR-mediated control of β-cell differentiation via apical polarity is also conserved in human neurogenin3 cells. We provide insight into how ligand-specific EGFR signalling coordinates epithelial morphogenesis and cell differentiation via apical polarity dynamics.
2 Communities
1 Members
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17 MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
FUCCI tracking shows cell-cycle-dependent Neurog3 variation in pancreatic progenitors.
Bechard ME, Bankaitis ED, Ustione A, Piston DW, Magnuson MA, Wright CVE
(2017) Genesis 55:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cells, Cultured, Embryonic Stem Cells, Green Fluorescent Proteins, Islets of Langerhans, Mice, Nerve Tissue Proteins
Show Abstract · Added September 5, 2017
During pancreas organogenesis, Neurog3 endocrine-committing cells are generated from a population of Sox9 mitotic progenitors with only a low level of Neurog3 transcriptional activity (Neurog3 ). Low-level Neurog3 protein, in Neurog3 cells, is required to maintain their mitotic endocrine-lineage-primed status. Herein, we describe a Neurog3-driven FUCCI cell-cycle reporter (Neurog3 ) derived from a Neurog3 BAC transgenic reporter that functions as a loxed cassette acceptor (LCA). In cycling Sox9 Neurog3 progenitors, the majority of cells in S-G -M phases have undetectable levels of Neurog3 with increased expression of endocrine progenitor markers, while those in G have low Neurog3 levels with increased expression of endocrine differentiation markers. These findings support a model in which variations in Neurog3 protein levels are coordinated with cell-cycle phase progression in Neurog3 progenitors with entrance into G triggering a concerted effort, beyond increasing Neurog3 levels, to maintain an endocrine-lineage-primed state by initiating expression of the downstream endocrine differentiation program prior to endocrine-commitment.
© 2017 Wiley Periodicals, Inc.
3 Communities
1 Members
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9 MeSH Terms
Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes 66: 2175-2187
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Calcium Signaling, Cell Adhesion, Cell Cycle Proteins, Cell Lineage, Cell Polarity, Gene Expression, Gene Expression Regulation, Insulin-Secreting Cells, KATP Channels, Mice, Pancreatic Polypeptide-Secreting Cells, S100 Calcium Binding Protein A6, S100 Calcium-Binding Protein A4, S100 Proteins, Sulfonylurea Receptors
Show Abstract · Added June 2, 2017
We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
© 2017 by the American Diabetes Association.
4 Communities
4 Members
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18 MeSH Terms
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.
Liang J, Le TH, Edwards DRV, Tayo BO, Gaulton KJ, Smith JA, Lu Y, Jensen RA, Chen G, Yanek LR, Schwander K, Tajuddin SM, Sofer T, Kim W, Kayima J, McKenzie CA, Fox E, Nalls MA, Young JH, Sun YV, Lane JM, Cechova S, Zhou J, Tang H, Fornage M, Musani SK, Wang H, Lee J, Adeyemo A, Dreisbach AW, Forrester T, Chu PL, Cappola A, Evans MK, Morrison AC, Martin LW, Wiggins KL, Hui Q, Zhao W, Jackson RD, Ware EB, Faul JD, Reiner AP, Bray M, Denny JC, Mosley TH, Palmas W, Guo X, Papanicolaou GJ, Penman AD, Polak JF, Rice K, Taylor KD, Boerwinkle E, Bottinger EP, Liu K, Risch N, Hunt SC, Kooperberg C, Zonderman AB, Laurie CC, Becker DM, Cai J, Loos RJF, Psaty BM, Weir DR, Kardia SLR, Arnett DK, Won S, Edwards TL, Redline S, Cooper RS, Rao DC, Rotter JI, Rotimi C, Levy D, Chakravarti A, Zhu X, Franceschini N
(2017) PLoS Genet 13: e1006728
MeSH Terms: African Americans, Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Pressure, Cadherins, Case-Control Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Membrane Proteins, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide
Show Abstract · Added March 14, 2018
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
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16 MeSH Terms
The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1.
Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR
(2017) Cell Death Differ 24: 855-865
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Communication, Cell Count, Cell Differentiation, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Regulation, HT29 Cells, Humans, Ileum, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Paneth Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-3, Receptors, G-Protein-Coupled, Stem Cell Niche, Stem Cells
Show Abstract · Added October 16, 2018
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche. Intestinal epithelial ErbB3 knockout caused precocious appearance of PCs as early as postnatal day 7, and substantially increased the number of mature PCs in adult mouse ileum. ErbB3 loss had no effect on other secretory lineages, but increased expression of the ISC marker Lgr5. ErbB3-null intestines had elevated levels of the Atoh1 transcription factor, which is required for secretory fate determination, while Atoh1 cells had reduced ErbB3, suggesting reciprocal negative regulation. ErbB3-null intestinal progenitor cells showed reduced activation of the PI3K-Akt and ERK MAPK pathways. Inhibiting these pathways in HT29 cells increased levels of ATOH1 and the PC marker LYZ. Conversely, ErbB3 activation suppressed LYZ and ATOH1 in a PI3K-dependent manner. Expansion of the PC compartment in ErbB3-null intestines was accompanied with elevated ER stress and inflammation markers, raising the possibility that negative regulation of PCs by ErbB3 is necessary to maintain homeostasis. Taken together, our data suggest that ErbB3 restricts PC numbers through PI3K-mediated suppression of Atoh1 levels leading to inhibition of PC differentiation, with important implications for regulation of the ISC niche.
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MeSH Terms
Maturity and age influence chief cell ability to transdifferentiate into metaplasia.
Weis VG, Petersen CP, Weis JA, Meyer AR, Choi E, Mills JC, Goldenring JR
(2017) Am J Physiol Gastrointest Liver Physiol 312: G67-G76
MeSH Terms: Age Factors, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Lineage, Cell Proliferation, Cell Transdifferentiation, Chief Cells, Gastric, Gastric Mucosa, Metaplasia, Mice, Mice, Knockout, Parietal Cells, Gastric, Peptides, Stomach
Show Abstract · Added April 18, 2017
The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1 mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss. Mist1 mice treated with DMP-777 showed fewer chief cell to SPEM transitions. Mist1 mice treated with L635 demonstrated significantly fewer proliferative SPEM cells compared with control mice. Thus immature chief cells were unable to transdifferentiate efficiently into SPEM after acute parietal cell loss. To determine whether chief cell age affects transdifferentiation into SPEM, we used tamoxifen to induce YFP expression in chief cells of Mist1;Rosa mice and subsequently treated the cells with L635 to induce SPEM at 1 to 3.5 mo after tamoxifen treatment. After L635 treatment to induce acute parietal cell loss, 43% of all YFP-positive cells at 1 mo posttamoxifen were SPEM cells, of which 44% of these YFP-positive SPEM cells were proliferative. By 2 mo after tamoxifen induction, only 24% of marked SPEM cells were proliferating. However, by 3.5 mo after tamoxifen induction, only 12% of marked chief cells transdifferentiated into SPEM and none were proliferative. Thus, as chief cells age, they lose their ability to transdifferentiate into SPEM and proliferate. Therefore, both functional maturation and age limit chief cell plasticity.
NEW & NOTEWORTHY - Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of chief cells. Nevertheless, the intrinsic properties of chief cells that influence transdifferentiation have been largely unknown. We now report that the ability to transdifferentiate into SPEM is impaired in chief cells that lack full functional maturation, and as chief cells age, they lose their ability to transdifferentiate. Thus chief cell plasticity is dependent on both cell age and maturation.
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14 MeSH Terms