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Michael S. German - One of the best experts on this subject based on the ideXlab platform.

  • homeodomain Transcription Factor Nkx2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors
    Endocrine-related Cancer, 2008
    Co-Authors: Yucheng Wang, Emerick Gallegoarteche, Gioia Iezza, Xiaochen Yuan, Mary Matli, Supin Choo, Marlene B Zuraek, Ravi Gogia, Francis C Lynn, Michael S. German
    Abstract:

    The homeodomain Transcription Factor Nkx2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that Nkx2.2 is important for NE differentiation in normal and neoplastic gut. Nkx2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of Nkx2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (-/-) mice was examined by IF and real-time (RT)-PCR. Nkx2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. Nkx2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting Nkx2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (-/-) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. Nkx2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude Nkx2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.

  • Mice lacking the homeodomain Transcription Factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells
    Development (Cambridge England), 1998
    Co-Authors: Lori Sussel, J. Kalamaras, Dennis J. Hartigan-o’connor, Juanito J. Meneses, Roger A. Pedersen, John L.r. Rubenstein, Michael S. German
    Abstract:

    The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: alpha beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of Transcription Factors, the specific roles of these Factors in early cell-type specification and differentiation remain elusive. Nkx2.2 is a member of the mammalian NK2 homeobox Transcription Factor family that is expressed in the ventral CNS and the pancreas. Within the pancreas, we demonstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells. In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth. Immunohistochemical analysis reveals that the mutant embryos lack insulin-producing beta cells and have fewer glucagon-producing alpha cells and PP cells. Remarkably, in the mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones. These cells express some beta cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state.

Johan Ericson - One of the best experts on this subject based on the ideXlab platform.

  • a homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube
    Cell, 2000
    Co-Authors: James Briscoe, Thomas M Jessell, Alessandra Pierani, Johan Ericson
    Abstract:

    Provided are genetically engineered cells comprising a neural stem cell and retroviral expression system in the neural stem cell and retroviral expression system in the neural stem cell, which is capable of expressing homeodomain Transcription Factor Nkx6.1 protein but does not express homeodomain Transcription Factor Irx3 protein or homeodomain Transcription Factor Nkx2.2 protein; which is capable of expressing homeodomain Transcription Factor Nkx6.1 protein and homeodomain Transcription Factor Irx3 protein; and which is capable of expressing homeodomain Transcription Factor Nkx2.2 protein or homeodomain Transcription Factor Nkx2.9 protein. Also provided are methods of generating such genetically engineered motor neurons, V2 neurons, and V3 neurons. Also provided are methods of treating subjects having a motor neuron injury or a motor neuron disease comprising implanting in injured/diseased neural tissue of the subject any of the provided genetically engineered cells, administering to such neural tissue retroviral expression systems which are capable of expressing the appropriate homeodomain protein(s), or transfecting neural stem cells with a retroviral vector, which is capable of expressing the required homeodomain Transcription Factor protein(s). Provided is a method of determining whether a chemical compound affects the generation of a motor neuron from a neural stem cell.

Abu Saleh Md Moin - One of the best experts on this subject based on the ideXlab platform.

  • characterization of non hormone expressing endocrine cells in fetal and infant human pancreas
    Frontiers in Endocrinology, 2019
    Co-Authors: Abu Saleh Md Moin, Chiara Montemurro, Kylie Zeng, Megan Cory, Megan Nguyen, Shweta Kulkarni, Helga Fritsch, Juris J Meier, Sangeeta Dhawan
    Abstract:

    Context: Previously, we identified chromograninA positive hormone-negative (CPHN) cells in high frequency in human fetal and neonatal pancreas, likely representing nascent endocrine precursor cells. Here, we characterize the putative endocrine fate and replicative status of these newly formed cells. Objective: To establish the replicative frequency and Transcriptional identity of CPHN cells, extending our observation on CPHN cell frequency to a larger cohort of fetal and infant pancreas. Design, Setting, and Participants: 8 fetal, 19 infant autopsy pancreata were evaluated for CPHN cell frequency; 12 fetal, 24 infant/child pancreata were evaluated for CPHN replication and identity. Results: CPHN cell frequency decreased 84% (islets) and 42% (clusters) from fetal to infant life. Unlike the beta-cells at this stage, CPHN cells were rarely observed to replicate (0.2 ± 0.1 vs. 4.7 ± 1.0%, CPHN vs. islet hormone positive cell replication, p < 0.001), indicated by the lack of Ki67 expression in CPHN cells whether located in the islets or in small clusters, and with no detectable difference between fetal and infant groups. While the majority of CPHN cells express (in overall compartments of pancreas) the pan-endocrine Transcription Factor Nkx2.2 and beta-cell specific NKX6.1 in comparable frequency in fetal and infant/child cases (81.9 ± 6.3 vs. 82.8 ± 3.8% NKX6.1+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.9; 88.0 ± 4.7 vs. 82.1 ± 5.3% Nkx2.2+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.4), the frequency of clustered CPHN cells expressing NKX6.1 or Nkx2.2 is lower in infant/child vs. fetal cases (1.2 ± 0.3 vs. 16.7 ± 4.7 clustered NKX6.1+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01; 2.7 ± 1.0 vs. 16.0 ± 4.0 clustered Nkx2.2+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01). Conclusions: The frequency of CPHN cells declines steeply from fetal to infant life, presumably as they differentiate to hormone-expressing cells. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells. Precis : CPHN cell frequency declines steeply from fetal to infant life, as they mature to hormone expression. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.

  • Image_7_Characterization of Non-hormone Expressing Endocrine Cells in Fetal and Infant Human Pancreas.jpg
    2019
    Co-Authors: Abu Saleh Md Moin, Chiara Montemurro, Kylie Zeng, Megan Cory, Megan Nguyen, Shweta Kulkarni, Helga Fritsch, Juris J Meier, Sangeeta Dhawan, Robert A. Rizza
    Abstract:

    Context: Previously, we identified chromograninA positive hormone-negative (CPHN) cells in high frequency in human fetal and neonatal pancreas, likely representing nascent endocrine precursor cells. Here, we characterize the putative endocrine fate and replicative status of these newly formed cells.Objective: To establish the replicative frequency and Transcriptional identity of CPHN cells, extending our observation on CPHN cell frequency to a larger cohort of fetal and infant pancreas.Design, Setting, and Participants: 8 fetal, 19 infant autopsy pancreata were evaluated for CPHN cell frequency; 12 fetal, 24 infant/child pancreata were evaluated for CPHN replication and identity.Results: CPHN cell frequency decreased 84% (islets) and 42% (clusters) from fetal to infant life. Unlike the beta-cells at this stage, CPHN cells were rarely observed to replicate (0.2 ± 0.1 vs. 4.7 ± 1.0%, CPHN vs. islet hormone positive cell replication, p < 0.001), indicated by the lack of Ki67 expression in CPHN cells whether located in the islets or in small clusters, and with no detectable difference between fetal and infant groups. While the majority of CPHN cells express (in overall compartments of pancreas) the pan-endocrine Transcription Factor Nkx2.2 and beta-cell specific NKX6.1 in comparable frequency in fetal and infant/child cases (81.9 ± 6.3 vs. 82.8 ± 3.8% NKX6.1+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.9; 88.0 ± 4.7 vs. 82.1 ± 5.3% Nkx2.2+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.4), the frequency of clustered CPHN cells expressing NKX6.1 or Nkx2.2 is lower in infant/child vs. fetal cases (1.2 ± 0.3 vs. 16.7 ± 4.7 clustered NKX6.1+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01; 2.7 ± 1.0 vs. 16.0 ± 4.0 clustered Nkx2.2+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01).Conclusions: The frequency of CPHN cells declines steeply from fetal to infant life, presumably as they differentiate to hormone-expressing cells. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.Precis: CPHN cell frequency declines steeply from fetal to infant life, as they mature to hormone expression. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.

  • Table_1_Characterization of Non-hormone Expressing Endocrine Cells in Fetal and Infant Human Pancreas.DOCX
    2019
    Co-Authors: Abu Saleh Md Moin, Chiara Montemurro, Kylie Zeng, Megan Cory, Megan Nguyen, Shweta Kulkarni, Helga Fritsch, Juris J Meier, Sangeeta Dhawan, Robert A. Rizza
    Abstract:

    Context: Previously, we identified chromograninA positive hormone-negative (CPHN) cells in high frequency in human fetal and neonatal pancreas, likely representing nascent endocrine precursor cells. Here, we characterize the putative endocrine fate and replicative status of these newly formed cells.Objective: To establish the replicative frequency and Transcriptional identity of CPHN cells, extending our observation on CPHN cell frequency to a larger cohort of fetal and infant pancreas.Design, Setting, and Participants: 8 fetal, 19 infant autopsy pancreata were evaluated for CPHN cell frequency; 12 fetal, 24 infant/child pancreata were evaluated for CPHN replication and identity.Results: CPHN cell frequency decreased 84% (islets) and 42% (clusters) from fetal to infant life. Unlike the beta-cells at this stage, CPHN cells were rarely observed to replicate (0.2 ± 0.1 vs. 4.7 ± 1.0%, CPHN vs. islet hormone positive cell replication, p < 0.001), indicated by the lack of Ki67 expression in CPHN cells whether located in the islets or in small clusters, and with no detectable difference between fetal and infant groups. While the majority of CPHN cells express (in overall compartments of pancreas) the pan-endocrine Transcription Factor Nkx2.2 and beta-cell specific NKX6.1 in comparable frequency in fetal and infant/child cases (81.9 ± 6.3 vs. 82.8 ± 3.8% NKX6.1+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.9; 88.0 ± 4.7 vs. 82.1 ± 5.3% Nkx2.2+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.4), the frequency of clustered CPHN cells expressing NKX6.1 or Nkx2.2 is lower in infant/child vs. fetal cases (1.2 ± 0.3 vs. 16.7 ± 4.7 clustered NKX6.1+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01; 2.7 ± 1.0 vs. 16.0 ± 4.0 clustered Nkx2.2+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01).Conclusions: The frequency of CPHN cells declines steeply from fetal to infant life, presumably as they differentiate to hormone-expressing cells. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.Precis: CPHN cell frequency declines steeply from fetal to infant life, as they mature to hormone expression. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.

Lori Sussel - One of the best experts on this subject based on the ideXlab platform.

  • Transcription Factor occupancy of the insulin gene in vivo evidence for direct regulation by Nkx2.2
    Journal of Biological Chemistry, 2003
    Co-Authors: Michelle A Cissell, Lori Sussel, Li Zhao, Eva Henderson, Roland Stein
    Abstract:

    Consensus-binding sites for many Transcription Factors are relatively non-selective and found at high frequency within the genome. This raises the possibility that Factors that are capable of binding to a cis-acting element in vitro and regulating Transcription from a transiently transfected plasmid, which would not have higher order chromatin structure, may not occupy this site within the endogenous gene. Closed chromatin structure and competition from another DNA-binding protein with similar nucleotide specificity are two possible mechanisms by which a Transcription Factor may be excluded from a potential binding sitein vivo. Multiple Transcription Factors, including Pdx-1, BETA-2, and Pax6, have been implicated in expression of the insulin gene in pancreatic β cells. In this study, the chromatin immunoprecipitation assay has been used to show that these Factors do, in fact, bind to insulin control region sequences in intact β cells. In addition, another key islet-enriched Transcription Factor, Nkx2.2, was found to occupy this region using the chromatin immunoprecipitation assay. In vitro DNA-binding and transient transfection assays defined how Nkx2.2 affected insulin gene expression. Pdx-1 was also shown to bind within a region of the endogenous islet amyloid polypeptide, pax-4, and glucokinase genes that were associated with control in vitro. Because Pdx-1 does not regulate gene Transcription in isolation, these sequences were examined for occupancy by the other insulin Transcriptional regulators. BETA-2, Pax6, and Nkx2.2 were also found to bind to amyloid polypeptide, glucokinase, andpax-4 control sequences in vivo. These studies reveal the broad application of the Pdx-1, BETA-2, Pax6, and Nkx2.2 Transcription Factors in regulating expression of genes selectively expressed in islet β cells.

  • Mice lacking the homeodomain Transcription Factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells
    Development (Cambridge England), 1998
    Co-Authors: Lori Sussel, J. Kalamaras, Dennis J. Hartigan-o’connor, Juanito J. Meneses, Roger A. Pedersen, John L.r. Rubenstein, Michael S. German
    Abstract:

    The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: alpha beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of Transcription Factors, the specific roles of these Factors in early cell-type specification and differentiation remain elusive. Nkx2.2 is a member of the mammalian NK2 homeobox Transcription Factor family that is expressed in the ventral CNS and the pancreas. Within the pancreas, we demonstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells. In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth. Immunohistochemical analysis reveals that the mutant embryos lack insulin-producing beta cells and have fewer glucagon-producing alpha cells and PP cells. Remarkably, in the mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones. These cells express some beta cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state.

Erik Boddeke - One of the best experts on this subject based on the ideXlab platform.

  • olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes
    Stem Cells, 2006
    Co-Authors: Sjef Copray, Veerakumar Balasubramaniyan, Josien Levenga, Jorick De Bruijn, Robert S B Liem, Erik Boddeke
    Abstract:

    Differentiation induction of neural stem cells (NSCs) into oligodendrocytes during embryogenesis is the result of a complex interaction between local induction Factors and intracellular Transcription Factors. At the early stage of differentiation, in particular, the helix-loop-helix Transcription Factors Olig1 and Olig2 have been shown to be essential for oligodendrocyte lineage determination. In view of the possible application of NSCs as a source for remyelinating cell transplants in demyelinating diseases (e.g., multiple sclerosis), in vitro procedures need to be developed to drive the oligodendrocyte differentiation process. Mere culture in medium supplemented with major embryonic oligodendrogenic induction Factors, such as Sonic hedgehog, results in oligodendrocyte differentiation of only about 10% of NSCs. We previously showed that induction of Olig1 expression by gene transfection could indeed initiate the first stage of oligodendrocyte differentiation in NSCs, but appeared to be unable to generate fully mature, functional oligodendrocytes. In this study, we transfected NSCs isolated from the embryonic mouse brain with the Olig2 gene and found that the introduced overexpression of Olig2 could induce the development of fully mature oligodendrocytes expressing the Transcription Factor Nkx2.2 and all major myelin-specific proteins. Moreover, Olig2-transfected NSCs, in contrast to nontransfected NSCs, developed into actively remyelinating oligodendrocytes after transplantation into the corpus callo-sum of long-term cuprizonefed mice, an animal model for demyelination. Our results show that transfection of genes encoding for oligodendrogenic Transcription Factors can be an efficient way to induce the differentiation of NSCs into functional oligodendrocytes.