The Experts below are selected from a list of 12 Experts worldwide ranked by ideXlab platform
Lori Sussel - One of the best experts on this subject based on the ideXlab platform.
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regulation of neurod1 contributes to the lineage potential of neurogenin3 endocrine precursor Cells in the pancreas
PLOS Genetics, 2013Co-Authors: Teresa L Mastracci, Lori Sussel, Keith R. Anderson, James B PapizanAbstract:During pancreatic development, transcription factor cascades gradually commit precursor populations to the different endocrine Cell fate pathways. Although mutational analyses have defined the functions of many individual pancreatic transcription factors, the integrative transcription factor networks required to regulate lineage specification, as well as their sites of action, are poorly understood. In this study, we investigated where and how the transcription factors Nkx2.2 and Neurod1 genetically interact to differentially regulate endocrine Cell specification. In an Nkx2.2 null background, we conditionally deleted Neurod1 in the Pdx1+ pancreatic progenitor Cells, the Neurog3+ endocrine progenitor Cells, or the glucagon+ alpha Cells. These studies determined that, in the absence of Nkx2.2 activity, removal of Neurod1 from the Pdx1+ or Neurog3+ progenitor populations is sufficient to reestablish the specification of the PP and Epsilon Cell lineages. Alternatively, in the absence of Nkx2.2, removal of Neurod1 from the Pdx1+ pancreatic progenitor population, but not the Neurog3+ endocrine progenitor Cells, restores alpha Cell specification. Subsequent in vitro reporter assays demonstrated that Nkx2.2 represses Neurod1 in alpha Cells. Based on these findings, we conclude that, although Nkx2.2 and Neurod1 are both necessary to promote beta Cell differentiation, Nkx2.2 must repress Neurod1 in a Pdx1+ pancreatic progenitor population to appropriately commit a subset of Neurog3+ endocrine progenitor Cells to the alpha Cell lineage. These results are consistent with the proposed idea that Neurog3+ endocrine progenitor Cells represent a heterogeneous population of unipotent Cells, each restricted to a particular endocrine lineage.
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nkx2 2 and arx genetically interact to regulate pancreatic endocrine Cell development and endocrine hormone expression
Developmental Biology, 2011Co-Authors: Teresa L Mastracci, Crystal L Wilcox, Luis Arnes, Casandra Panea, Jeffrey A Golden, Catherine Lee May, Lori SusselAbstract:Nkx2.2 and Arx are essential pancreatic transcription factors. Nkx2.2 is necessary for the appropriate specification of the islet alpha, beta, PP and Epsilon Cell lineages, whereas Arx is required to form the correct ratio of alpha, beta, delta and PP Cells. To begin to understand the cooperative functions of Nkx2.2 and Arx in the development of endocrine Cell lineages, we generated progenitor Cell-specific deletions of Arx on the Nkx2.2 null background. The analysis of these mutants demonstrates that expansion of the ghrelin Cell population in the Nkx2.2 null pancreas is not dependent on Arx; however, Arx is necessary for the upregulation of ghrelin mRNA levels in Nkx2.2 mutant Epsilon Cells. Alternatively, in the absence of Arx, delta Cell numbers are increased and Nkx2.2 becomes essential for the repression of somatostatin gene expression. Interestingly, the dysregulation of ghrelin and somatostatin expression in the Nkx2.2/Arx compound mutant (Nkx2.2null;ArxΔpanc) results in the appearance of ghrelin+/somatostatin+ co-expressing Cells. These compound mutants also revealed a genetic interaction between Nkx2.2 and Arx in the regulation of the PP Cell lineage; the PP Cell population is reduced when Nkx2.2 is deleted but is restored back to wildtype numbers in the Nkx2.2null;ArxΔpanc mutant. Moreover, conditional deletion of Arx in specific pancreatic Cell populations established that the functions of Arx are necessary in the Neurog3+ endocrine progenitors. Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the endocrine progenitor Cells that ensure the correct specification and regulation of endocrine hormone-producing Cells.
Palle Serup - One of the best experts on this subject based on the ideXlab platform.
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Genetic determinants of pancreatic Epsilon-Cell development.
Developmental Biology, 2005Co-Authors: R Scott Heller, Gerard Gradwohl, Marjorie Jenny, Patrick Collombat, Ahmed Mansouri, Catherine Tomasetto, Ole D Madsen, Georg Mellitzer, Palle SerupAbstract:Recently, the expression of the peptide hormone ghrelin was detected in alpha-Cells of the islets of Langerhans as well as in Epsilon-Cells, a newly discovered endocrine Cell type, but it remains unclear how the latter is related in lineage to the four classical islet Cell types, alpha-, beta-, delta-, and PP-Cells. Here, we provide further evidence that ghrelin is predominantly produced in the alpha-Cells of mouse islets but also in single hormone ghrelin-secreting Epsilon-Cells. We additionally demonstrate that pancreatic Epsilon-Cells derive from Neurogenin3-expressing precursor Cells and their genesis depends on Neurogenin3 activity. Furthermore, our data indicate that the number of ghrelin-producing Cells is differentially regulated during pancreas morphogenesis by the homeodomain-containing transcription factors Arx, Pax4, and Pax6. Arx mutants lack ghrelin+ glucagon+ alpha-Cells whereas Pax4 mutants develop an excess of these Cells. Importantly, the ghrelin+ glucagon- Epsilon-Cell population is not affected following Arx or Pax4 disruption. In contrast, the loss of Pax6 provokes an unexpected increase of the ghrelin+ glucagon- Epsilon-Cell number which is not due to increased proliferation. Thus, we demonstrate that the development of ghrelin-producing Cells is differentially dependent on Neurogenin3 in different domains of the gastrointestinal tract and that, in the endocrine pancreas, Epsilon-Cell genesis does not require Arx or Pax4 activities but is antagonized by Pax6.
Teresa L Mastracci - One of the best experts on this subject based on the ideXlab platform.
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regulation of neurod1 contributes to the lineage potential of neurogenin3 endocrine precursor Cells in the pancreas
PLOS Genetics, 2013Co-Authors: Teresa L Mastracci, Lori Sussel, Keith R. Anderson, James B PapizanAbstract:During pancreatic development, transcription factor cascades gradually commit precursor populations to the different endocrine Cell fate pathways. Although mutational analyses have defined the functions of many individual pancreatic transcription factors, the integrative transcription factor networks required to regulate lineage specification, as well as their sites of action, are poorly understood. In this study, we investigated where and how the transcription factors Nkx2.2 and Neurod1 genetically interact to differentially regulate endocrine Cell specification. In an Nkx2.2 null background, we conditionally deleted Neurod1 in the Pdx1+ pancreatic progenitor Cells, the Neurog3+ endocrine progenitor Cells, or the glucagon+ alpha Cells. These studies determined that, in the absence of Nkx2.2 activity, removal of Neurod1 from the Pdx1+ or Neurog3+ progenitor populations is sufficient to reestablish the specification of the PP and Epsilon Cell lineages. Alternatively, in the absence of Nkx2.2, removal of Neurod1 from the Pdx1+ pancreatic progenitor population, but not the Neurog3+ endocrine progenitor Cells, restores alpha Cell specification. Subsequent in vitro reporter assays demonstrated that Nkx2.2 represses Neurod1 in alpha Cells. Based on these findings, we conclude that, although Nkx2.2 and Neurod1 are both necessary to promote beta Cell differentiation, Nkx2.2 must repress Neurod1 in a Pdx1+ pancreatic progenitor population to appropriately commit a subset of Neurog3+ endocrine progenitor Cells to the alpha Cell lineage. These results are consistent with the proposed idea that Neurog3+ endocrine progenitor Cells represent a heterogeneous population of unipotent Cells, each restricted to a particular endocrine lineage.
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nkx2 2 and arx genetically interact to regulate pancreatic endocrine Cell development and endocrine hormone expression
Developmental Biology, 2011Co-Authors: Teresa L Mastracci, Crystal L Wilcox, Luis Arnes, Casandra Panea, Jeffrey A Golden, Catherine Lee May, Lori SusselAbstract:Nkx2.2 and Arx are essential pancreatic transcription factors. Nkx2.2 is necessary for the appropriate specification of the islet alpha, beta, PP and Epsilon Cell lineages, whereas Arx is required to form the correct ratio of alpha, beta, delta and PP Cells. To begin to understand the cooperative functions of Nkx2.2 and Arx in the development of endocrine Cell lineages, we generated progenitor Cell-specific deletions of Arx on the Nkx2.2 null background. The analysis of these mutants demonstrates that expansion of the ghrelin Cell population in the Nkx2.2 null pancreas is not dependent on Arx; however, Arx is necessary for the upregulation of ghrelin mRNA levels in Nkx2.2 mutant Epsilon Cells. Alternatively, in the absence of Arx, delta Cell numbers are increased and Nkx2.2 becomes essential for the repression of somatostatin gene expression. Interestingly, the dysregulation of ghrelin and somatostatin expression in the Nkx2.2/Arx compound mutant (Nkx2.2null;ArxΔpanc) results in the appearance of ghrelin+/somatostatin+ co-expressing Cells. These compound mutants also revealed a genetic interaction between Nkx2.2 and Arx in the regulation of the PP Cell lineage; the PP Cell population is reduced when Nkx2.2 is deleted but is restored back to wildtype numbers in the Nkx2.2null;ArxΔpanc mutant. Moreover, conditional deletion of Arx in specific pancreatic Cell populations established that the functions of Arx are necessary in the Neurog3+ endocrine progenitors. Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the endocrine progenitor Cells that ensure the correct specification and regulation of endocrine hormone-producing Cells.
R Scott Heller - One of the best experts on this subject based on the ideXlab platform.
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Genetic determinants of pancreatic Epsilon-Cell development.
Developmental Biology, 2005Co-Authors: R Scott Heller, Gerard Gradwohl, Marjorie Jenny, Patrick Collombat, Ahmed Mansouri, Catherine Tomasetto, Ole D Madsen, Georg Mellitzer, Palle SerupAbstract:Recently, the expression of the peptide hormone ghrelin was detected in alpha-Cells of the islets of Langerhans as well as in Epsilon-Cells, a newly discovered endocrine Cell type, but it remains unclear how the latter is related in lineage to the four classical islet Cell types, alpha-, beta-, delta-, and PP-Cells. Here, we provide further evidence that ghrelin is predominantly produced in the alpha-Cells of mouse islets but also in single hormone ghrelin-secreting Epsilon-Cells. We additionally demonstrate that pancreatic Epsilon-Cells derive from Neurogenin3-expressing precursor Cells and their genesis depends on Neurogenin3 activity. Furthermore, our data indicate that the number of ghrelin-producing Cells is differentially regulated during pancreas morphogenesis by the homeodomain-containing transcription factors Arx, Pax4, and Pax6. Arx mutants lack ghrelin+ glucagon+ alpha-Cells whereas Pax4 mutants develop an excess of these Cells. Importantly, the ghrelin+ glucagon- Epsilon-Cell population is not affected following Arx or Pax4 disruption. In contrast, the loss of Pax6 provokes an unexpected increase of the ghrelin+ glucagon- Epsilon-Cell number which is not due to increased proliferation. Thus, we demonstrate that the development of ghrelin-producing Cells is differentially dependent on Neurogenin3 in different domains of the gastrointestinal tract and that, in the endocrine pancreas, Epsilon-Cell genesis does not require Arx or Pax4 activities but is antagonized by Pax6.
Georg Mellitzer - One of the best experts on this subject based on the ideXlab platform.
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Genetic determinants of pancreatic Epsilon-Cell development.
Developmental Biology, 2005Co-Authors: R Scott Heller, Gerard Gradwohl, Marjorie Jenny, Patrick Collombat, Ahmed Mansouri, Catherine Tomasetto, Ole D Madsen, Georg Mellitzer, Palle SerupAbstract:Recently, the expression of the peptide hormone ghrelin was detected in alpha-Cells of the islets of Langerhans as well as in Epsilon-Cells, a newly discovered endocrine Cell type, but it remains unclear how the latter is related in lineage to the four classical islet Cell types, alpha-, beta-, delta-, and PP-Cells. Here, we provide further evidence that ghrelin is predominantly produced in the alpha-Cells of mouse islets but also in single hormone ghrelin-secreting Epsilon-Cells. We additionally demonstrate that pancreatic Epsilon-Cells derive from Neurogenin3-expressing precursor Cells and their genesis depends on Neurogenin3 activity. Furthermore, our data indicate that the number of ghrelin-producing Cells is differentially regulated during pancreas morphogenesis by the homeodomain-containing transcription factors Arx, Pax4, and Pax6. Arx mutants lack ghrelin+ glucagon+ alpha-Cells whereas Pax4 mutants develop an excess of these Cells. Importantly, the ghrelin+ glucagon- Epsilon-Cell population is not affected following Arx or Pax4 disruption. In contrast, the loss of Pax6 provokes an unexpected increase of the ghrelin+ glucagon- Epsilon-Cell number which is not due to increased proliferation. Thus, we demonstrate that the development of ghrelin-producing Cells is differentially dependent on Neurogenin3 in different domains of the gastrointestinal tract and that, in the endocrine pancreas, Epsilon-Cell genesis does not require Arx or Pax4 activities but is antagonized by Pax6.