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Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells.
Pan FC, Brissova M, Powers AC, Pfaff S, Wright CV
(2015) Development 142: 3637-48
MeSH Terms: Animals, Cell Transdifferentiation, Cellular Senescence, Diabetes Mellitus, Eye Proteins, Homeodomain Proteins, Humans, Hyperplasia, Insulin-Secreting Cells, Mice, PAX6 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Somatostatin-Secreting Cells, Transcription Factors
Show Abstract · Added December 28, 2015
Homozygous Mnx1 mutation causes permanent neonatal diabetes in humans, but via unknown mechanisms. Our systematic and longitudinal analysis of Mnx1 function during murine pancreas organogenesis and into the adult uncovered novel stage-specific roles for Mnx1 in endocrine lineage allocation and β-cell fate maintenance. Inactivation in the endocrine-progenitor stage shows that Mnx1 promotes β-cell while suppressing δ-cell differentiation programs, and is crucial for postnatal β-cell fate maintenance. Inactivating Mnx1 in embryonic β-cells (Mnx1(Δbeta)) caused β-to-δ-like cell transdifferentiation, which was delayed until postnatal stages. In the latter context, β-cells escaping Mnx1 inactivation unexpectedly upregulated Mnx1 expression and underwent an age-independent persistent proliferation. Escaper β-cells restored, but then eventually surpassed, the normal pancreatic β-cell mass, leading to islet hyperplasia in aged mice. In vitro analysis of islets isolated from Mnx1(Δbeta) mice showed higher insulin secretory activity and greater insulin mRNA content than in wild-type islets. Mnx1(Δbeta) mice also showed a much faster return to euglycemia after β-cell ablation, suggesting that the new β-cells derived from the escaper population are functional. Our findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy.
© 2015. Published by The Company of Biologists Ltd.
0 Communities
3 Members
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15 MeSH Terms
Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas.
Pan Z, Grizzle W, Hameed O
(2013) Am J Clin Pathol 140: 410-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Cadherins, Carbonic Anhydrase IX, Carbonic Anhydrases, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, PAX2 Transcription Factor, PAX8 Transcription Factor, Paired Box Transcription Factors, Receptor for Advanced Glycation End Products
Show Abstract · Added March 7, 2014
OBJECTIVES - To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases.
METHODS - Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8).
RESULTS - There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases.
CONCLUSIONS - Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs.
0 Communities
1 Members
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12 MeSH Terms
Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation.
Sugiyama T, Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK
(2013) Proc Natl Acad Sci U S A 110: 12691-6
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, DNA-Binding Proteins, Diabetes Mellitus, Female, Glucagon-Secreting Cells, Homeodomain Proteins, Insulin-Secreting Cells, Male, Mice, Mice, Transgenic, Nerve Tissue Proteins, Paired Box Transcription Factors, Stem Cells, Transcription Factors
Show Abstract · Added February 3, 2014
Developmental biology is challenged to reveal the function of numerous candidate genes implicated by recent genome-scale studies as regulators of organ development and diseases. Recapitulating organogenesis from purified progenitor cells that can be genetically manipulated would provide powerful opportunities to dissect such gene functions. Here we describe systems for reconstructing pancreas development, including islet β-cell and α-cell differentiation, from single fetal progenitor cells. A strict requirement for native genetic regulators of in vivo pancreas development, such as Ngn3, Arx, and Pax4, revealed the authenticity of differentiation programs in vitro. Efficient genetic screens permitted by this system revealed that Prdm16 is required for pancreatic islet development in vivo. Discovering the function of genes regulating pancreas development with our system should enrich strategies for regenerating islets for treating diabetes mellitus.
3 Communities
2 Members
1 Resources
16 MeSH Terms
Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes.
Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P
(2013) Dev Cell 26: 86-100
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Glucose, Cell Differentiation, Cell Lineage, Cell Movement, Cellular Reprogramming, Diabetes Mellitus, Experimental, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Glucagon-Secreting Cells, Homeodomain Proteins, Hypertrophy, Insulin-Secreting Cells, Mice, Nerve Tissue Proteins, Paired Box Transcription Factors, Pancreatic Ducts, Streptozocin
Show Abstract · Added August 14, 2013
It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Resources
19 MeSH Terms
DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction.
Neely MD, Litt MJ, Tidball AM, Li GG, Aboud AA, Hopkins CR, Chamberlin R, Hong CC, Ess KC, Bowman AB
(2012) ACS Chem Neurosci 3: 482-91
MeSH Terms: Adult, Animals, Bone Morphogenetic Proteins, Carrier Proteins, Child, Eye Proteins, Female, Gene Expression Regulation, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Male, Mice, Middle Aged, Neural Inhibition, Neural Stem Cells, Neurogenesis, Neurons, PAX6 Transcription Factor, Paired Box Transcription Factors, Pyrazoles, Quinolines, Repressor Proteins, SOXB1 Transcription Factors, Stem Cells
Show Abstract · Added August 25, 2013
Recent successes in deriving human-induced pluripotent stem cells (hiPSCs) allow for the possibility of studying human neurons derived from patients with neurological diseases. Concomitant inhibition of the BMP and TGF-β1 branches of the TGF-β signaling pathways by the endogenous antagonist, Noggin, and the small molecule SB431542, respectively, induces efficient neuralization of hiPSCs, a method known as dual-SMAD inhibition. The use of small molecule inhibitors instead of their endogenous counterparts has several advantages including lower cost, consistent activity, and the maintenance of xeno-free culture conditions. We tested the efficacy of DMH1, a highly selective small molecule BMP-inhibitor for its potential to replace Noggin in the neuralization of hiPSCs. We compare Noggin and DMH1-induced neuralization of hiPSCs by measuring protein and mRNA levels of pluripotency and neural precursor markers over a period of seven days. The regulation of five of the six markers assessed was indistinguishable in the presence of concentrations of Noggin or DMH1 that have been shown to effectively inhibit BMP signaling in other systems. We observed that by varying the DMH1 or Noggin concentration, we could selectively modulate the number of SOX1 expressing cells, whereas PAX6, another neural precursor marker, remained the same. The level and timing of SOX1 expression have been shown to affect neural induction as well as neural lineage. Our observations, therefore, suggest that BMP-inhibitor concentrations need to be carefully monitored to ensure appropriate expression levels of all transcription factors necessary for the induction of a particular neuronal lineage. We further demonstrate that DMH1-induced neural progenitors can be differentiated into β3-tubulin expressing neurons, a subset of which also express tyrosine hydroxylase. Thus, the combined use of DMH1, a highly specific BMP-pathway inhibitor, and SB431542, a TGF-β1-pathway specific inhibitor, provides us with the tools to independently regulate these two pathways through the exclusive use of small molecule inhibitors.
3 Communities
4 Members
0 Resources
25 MeSH Terms
Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma.
Hoshimoto S, Faries MB, Morton DL, Shingai T, Kuo C, Wang HJ, Elashoff R, Mozzillo N, Kelley MC, Thompson JF, Lee JE, Hoon DS
(2012) Ann Surg 255: 357-62
MeSH Terms: Adult, Aged, Antigens, Neoplasm, Biomarkers, Tumor, Cancer Vaccines, Chemotherapy, Adjuvant, Double-Blind Method, Female, Humans, MART-1 Antigen, Male, Melanoma, Middle Aged, Multivariate Analysis, Neoplasm Proteins, Neoplasm Staging, Neoplastic Cells, Circulating, PAX3 Transcription Factor, Paired Box Transcription Factors, Prognosis, Real-Time Polymerase Chain Reaction, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis
Show Abstract · Added February 16, 2016
OBJECTIVE - To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial.
BACKGROUND - Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment.
METHODS - After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables.
RESULTS - CTC biomarker(s) (≥ 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012).
CONCLUSION - CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients.
0 Communities
1 Members
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24 MeSH Terms
β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors.
Clark PE, Polosukhina D, Love H, Correa H, Coffin C, Perlman EJ, de Caestecker M, Moses HL, Zent R
(2011) Am J Pathol 179: 3045-55
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Cell Transformation, Neoplastic, Exons, Genes, ras, Humans, Inhibitor of Apoptosis Proteins, Kidney Neoplasms, Kidney Tubules, Proximal, MAP Kinase Signaling System, Mice, Mice, Transgenic, Mutation, Nuclear Proteins, PAX2 Transcription Factor, PAX8 Transcription Factor, Paired Box Transcription Factors, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Repressor Proteins, Signal Transduction, Survivin, Wilms Tumor, beta Catenin
Show Abstract · Added February 17, 2014
Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence of activated β-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing β-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, metastatic, multifocal primitive renal epithelial tumors that have the histologic and staining characteristics of the epithelial component of human WT. These highly malignant tumors have increased activation of the phosphatidylinositol 3-kinase-AKT and extracellular signal-regulated kinase pathways, increased expression of total and nuclear β-catenin, and increased downstream targets of this pathway, such as c-Myc and survivin. Thus, we developed a novel mouse model in which activated K-RAS synergizes with canonical Wnt/β-catenin signaling to form metastatic primitive renal epithelial tumors that mimic the epithelial component of human WT.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
4 Communities
5 Members
0 Resources
24 MeSH Terms
Diagnostic utility of PAX8, TTF-1 and napsin A for discriminating metastatic carcinoma from primary adenocarcinoma of the lung.
Ye J, Hameed O, Findeis-Hosey JJ, Fan L, Li F, McMahon LA, Yang Q, Wang HL, Xu H
(2012) Biotech Histochem 87: 30-4
MeSH Terms: Adenocarcinoma, Aspartic Acid Endopeptidases, Biomarkers, Tumor, DNA-Binding Proteins, Diagnosis, Differential, Humans, Immunohistochemistry, Lung Neoplasms, PAX8 Transcription Factor, Paired Box Transcription Factors, Transcription Factors
Show Abstract · Added March 21, 2014
TTF-1 and napsin A are useful biomarkers for differentiating primary lung adenocarcinoma from metastatic tumors. Studies have shown, however, that TTF-1 and napsin A also can be expressed in extrapulmonary carcinomas, and that a small fraction of primary lung adenocarcinomas do not co-express these two markers. We attempted to determine whether a tissue-specific transcriptional factor, PAX8, can help determine primary sites of lung carcinomas. Immunohistochemical stains for PAX8, TTF-1 and napsin A were performed on 103 cases of metastatic lung carcinomas from a variety of origins and 120 cases of primary lung adenocarcinomas. Our data demonstrated that all 103 metastatic carcinomas were negative for napsin A, while 14 (13.6%; four thyroid, two endometrium, three colon, one prostate, one salivary adenoid cystic, two renal cell carcinomas, and one ovary) showed weak to strong TTF-1 nuclear staining in 5-60% of the tumor cells. All primary lung adenocarcinomas were negative for PAX8, whereas 46 (44.7%) metastatic carcinomas from the kidney (29/33), ovary (6/8), endometrium (5/5), endocervix (1/1), thyroid (4/5) and urinary tract (1/3) were positive for PAX8. Our data demonstrate that of combined use of PAX8, TTF-1 and napsin A is reliable to separate reliably lung primary from metastatic tumors.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Functional interaction between Foxd3 and Pax3 in cardiac neural crest development.
Nelms BL, Pfaltzgraff ER, Labosky PA
(2011) Genesis 49: 10-23
MeSH Terms: Animals, Craniofacial Abnormalities, Embryo Loss, Forkhead Transcription Factors, Mice, Mice, Mutant Strains, Neural Crest, PAX3 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Sequence Deletion, Stem Cells, Thymus Gland, Truncus Arteriosus, Persistent
Show Abstract · Added March 31, 2011
The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
Copyright © 2010 Wiley-Liss, Inc.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Ripply3, a Tbx1 repressor, is required for development of the pharyngeal apparatus and its derivatives in mice.
Okubo T, Kawamura A, Takahashi J, Yagi H, Morishima M, Matsuoka R, Takada S
(2011) Development 138: 339-48
MeSH Terms: Animals, Base Sequence, Branchial Region, Chromosome Deletion, Chromosomes, Human, Pair 22, DNA Primers, Female, Gene Expression Regulation, Developmental, Heart Defects, Congenital, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Paired Box Transcription Factors, Phenotype, Pregnancy, Repressor Proteins, T-Box Domain Proteins
Show Abstract · Added December 9, 2016
The pharyngeal apparatus is a transient structure that gives rise to the thymus and the parathyroid glands and also contributes to the development of arteries and the cardiac outflow tract. A typical developmental disorder of the pharyngeal apparatus is the 22q11 deletion syndrome (22q11DS), for which Tbx1 is responsible. Here, we show that Ripply3 can modulate Tbx1 activity and plays a role in the development of the pharyngeal apparatus. Ripply3 expression is observed in the pharyngeal ectoderm and endoderm and overlaps with strong expression of Tbx1 in the caudal pharyngeal endoderm. Ripply3 suppresses transcriptional activation by Tbx1 in luciferase assays in vitro. Ripply3-deficient mice exhibit abnormal development of pharyngeal derivatives, including ectopic formation of the thymus and the parathyroid gland, as well as cardiovascular malformation. Corresponding with these defects, Ripply3-deficient embryos show hypotrophy of the caudal pharyngeal apparatus. Ripply3 represses Tbx1-induced expression of Pax9 in luciferase assays in vitro, and Ripply3-deficient embryos exhibit upregulated Pax9 expression. Together, our results show that Ripply3 plays a role in pharyngeal development, probably by regulating Tbx1 activity.
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20 MeSH Terms