Artículos de revistas: "Nkx2.2"

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Wei, Qiou, W. Keith Miskimins y Robin Miskimins. "Stage-specific Expression of Myelin Basic Protein in Oligodendrocytes Involves Nkx2.2-mediated Repression That Is Relieved by the Sp1 Transcription Factor". Journal of Biological Chemistry 280, n.º 16 (3 de febrero de 2005): 16284–94. http://dx.doi.org/10.1074/jbc.m500491200.

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The homeodomain-containing protein Nkx2.2 is critical for the development of oligodendrocyte lineage cells, but the target genes of Nkx2.2 regulation have not been identified. In the present study, we found that the myelin basic protein gene is one of the genes that is regulated by Nkx2.2. Expression of Nkx2.2 represses the expression of myelin basic protein in oligodendrocyte progenitors. Two regulatory elements in the myelin basic protein promoter were identified and found to interact with Nkx2.2in vitro. Despite their sequence divergence, both sites were involved in the Nkx2.2-mediated repression of the myelin basic protein promoter. Binding of Nkx2.2 also blocked and disrupted the binding of the transcriptional activator Purα to the myelin basic protein promoter. Additionally Nkx2.2 recruited a histone deacetylase 1-mSin3A complex to the myelin basic protein promoter. We also found that the transcription factor Sp1 was able to compete off the binding of Nkx2.2 to its consensus binding sitein vitroand reversed the repressive effect of Nkx2.2in vivo. Our data revealed a novel role for Nkx2.2 in preventing the precocious expression of myelin basic protein in immature oligodendrocytes. Based on this study and our previous reports, a model for myelin basic protein gene control is proposed.

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Sander, M., L. Sussel, J. Conners, D. Scheel, J. Kalamaras, F. Dela Cruz, V. Schwitzgebel, A. Hayes-Jordan y M. German. "Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas". Development 127, n.º 24 (15 de diciembre de 2000): 5533–40. http://dx.doi.org/10.1242/dev.127.24.5533.

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Most insulin-producing beta-cells in the fetal mouse pancreas arise during the secondary transition, a wave of differentiation starting at embryonic day 13. Here, we show that disruption of homeobox gene Nkx6.1 in mice leads to loss of beta-cell precursors and blocks beta-cell neogenesis specifically during the secondary transition. In contrast, islet development in Nkx6. 1/Nkx2.2 double mutant embryos is identical to Nkx2.2 single mutant islet development: beta-cell precursors survive but fail to differentiate into beta-cells throughout development. Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation.

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Kucenas, Sarah, Heather Snell y Bruce Appel. "nkx2.2a promotes specification and differentiation of a myelinating subset of oligodendrocyte lineage cells in zebrafish". Neuron Glia Biology 4, n.º 2 (mayo de 2008): 71–81. http://dx.doi.org/10.1017/s1740925x09990123.

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During development, multipotent neural precursors give rise to oligodendrocyte progenitor cells (OPCs), which migrate and divide to produce additional OPCs. Near the end of embryogenesis and during postnatal stages, many OPCs stop dividing and differentiate as myelinating oligodendrocytes, whereas others persist as nonmyelinating cells. Investigations of oligodendrocyte development in mice indicated that the Nkx2.2 transcription factor both limits the number of OPCs that are formed and subsequently promotes their differentiation, raising the possibility that Nkx2.2 plays a key role in determining myelinating versus nonmyelinating fate. We used in vivo time-lapse imaging and loss-of-function experiments in zebrafish to further explore formation and differentiation of oligodendrocyte lineage cells. Our data show that newly specified OPCs are heterogeneous with respect to gene expression and fate. Whereas some OPCs express the nkx2.2a gene and differentiate as oligodendrocytes, others that do not express nkx2.2a mostly remain as nonmyelinating OPCs. Similarly to mouse, loss of nkx2.2a function results in excess OPCs and delayed oligodendrocyte differentiation. Notably, excess OPCs are formed as a consequence of prolonged OPC production from neural precursor cells. We conclude that Nkx2.2 promotes timely specification and differentiation of myelinating oligodendrocyte lineage cells from species representing different vertebrate taxa.

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Qi, Yingchuan, Jun Cai, Yuanyuan Wu, Rui Wu, Jeffrey Lee, Hui Fu, Mahendra Rao, Lori Sussel, John Rubenstein y Mengsheng Qiu. "Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor". Development 128, n.º 14 (15 de julio de 2001): 2723–33. http://dx.doi.org/10.1242/dev.128.14.2723.

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Oligodendrocytes are derived from glial precursors that arise from the ventral neural tube early in development. In the developing chicken CNS, oligodendrocyte progenitors selectively express Nkx2.2 homeodomain transcription factor, raising the possibility that Nkx2.2 may directly regulate oligogliogenesis. In this study, we have examined Nkx2.2 expression in rodent glial precursors and studied the effect of a loss of Nkx2.2 on oligodendrocyte and astrocyte differentiation. We show that Nkx2.2 is also expressed in mammalian oligodendrocyte progenitors and that the differentiation of MBP-positive and PLP-DM20-positive oligodendrocytes is dramatically retarded in Nkx2.2-null mutants along the entire rostrocaudal axis. In contrast, no effect is seen on astrocytic differentiation. Interestingly, absence of Nkx2.2 expression leads to a ventral expansion of the Olig1/Olig2 expression in neuroepithelial cells into the Nkx2.2 domain and a consequent increase in the production of Olig1/Olig2-positive and platelet-derived growth factor receptor α-positive oligodendrocyte progenitors. These results strongly suggest that Nkx2.2 regulates the differentiation and/or maturation, but not the initial specification, of oligodendrocyte progenitors. Consistent with this suggestion, overproduction of Nkx2.2 protein in fibroblast cells can induce gene expression from the proteolipid protein promoter.

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Wang, Yu-Cheng, Emerick Gallego-Arteche, Gioia Iezza, Xiaochen Yuan, Mary R. Matli, Su-Pin Choo, Marlene B. Zuraek et al. "Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors". Endocrine-Related Cancer 16, n.º 1 (marzo de 2009): 267–79. http://dx.doi.org/10.1677/erc-08-0127.

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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.

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Sussel, L., J. Kalamaras, D. J. Hartigan-O'Connor, J. J. Meneses, R. A. Pedersen, J. L. Rubenstein y M. S. German. "Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells". Development 125, n.º 12 (15 de junio de 1998): 2213–21. http://dx.doi.org/10.1242/dev.125.12.2213.

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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.

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Fu, Hui, Yingchuan Qi, Min Tan, Jun Cai, Hirohide Takebayashi, Masato Nakafuku, William Richardson y Mengsheng Qiu. "Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of Olig2 and Nkx2.2 in the control of oligodendrocyte differentiation". Development 129, n.º 3 (1 de febrero de 2002): 681–93. http://dx.doi.org/10.1242/dev.129.3.681.

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In this study, we have investigated the relationship of Olig2+ and Nkx2.2+ oligodendrocyte progenitors (OLPs) by comparing the expression of Olig2 and Nkx2.2 in embryonic chicken and mouse spinal cords before and during the stages of oligodendrogenesis. At the stages of neurogenesis, Olig2 and Nkx2.2 are expressed in adjacent non-overlapping domains of ventral neuroepithelium. During oligodendrogenesis stages, these two domains generate distinct populations of OLPs. From the Olig2+ motoneuron precursor domain (pMN) arise the Olig2+/Pdgfra+ OLPs, whereas the Nkx2.2+ p3 domain give rise to Nkx2.2+ OLPs. Despite their distinct origins, both populations of OLPs eventually appear to co-express Olig2 and Nkx2.2 in the same cells. However, there is a species difference in the timing of acquiring Nkx2.2 expression by the Olig2+/Pdgfra+ OLPs. The co-expression of Nkx2.2 and Olig2 in OLPs is tightly associated with myelin gene expression in the normal and PDGFA–/– embryos, suggesting a cooperative role of these transcription factors in the control of oligodendrocyte differentiation. In support of this suggestion, inhibition of expression of these two transcription factors in culture by antisense oligonucleotides has an additive inhibitory effect on OLP differentiation and proteolipid protein (PLP) gene expression.

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Gross, Stefanie, Dina Balderes, Jing Liu, Samuel Asfaha, Guoqiang Gu, Timothy C. Wang y Lori Sussel. "Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential". American Journal of Physiology-Gastrointestinal and Liver Physiology 309, n.º 12 (15 de diciembre de 2015): G975—G987. http://dx.doi.org/10.1152/ajpgi.00244.2015.

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There are two major stem cell populations in the intestinal crypt region that express either Bmi1 or Lgr5; however, it has been shown that other populations in the crypt can regain stemness. In this study, we demonstrate that the transcription factor NK2 homeobox 2 (Nkx2.2) is expressed in enteroendocrine cells located in the villus and crypt of the intestinal epithelium and is coexpressed with the stem cell markers Bmi1 and Lgr5 in a subset of crypt cells. To determine whether Nkx2.2-expressing enteroendocrine cells display cellular plasticity and stem cell potential, we performed genetic lineage tracing of the Nkx2.2-expressing population using Nkx2.2Cre/+; R26RTomato mice. These studies demonstrated that Nkx2.2+ cells are able to give rise to all intestinal epithelial cell types in basal conditions. The proliferative capacity of Nkx2.2-expressing cells was also demonstrated in vitro using crypt organoid cultures. Injuring the intestine with irradiation, systemic inflammation, and colitis did not enhance the lineage potential of Nkx2.2-expressing cells. These findings demonstrate that a rare mature enteroendocrine cell subpopulation that is demarcated by Nkx2.2 expression display stem cell properties during normal intestinal epithelial homeostasis, but is not easily activated upon injury.

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Hill, Jonathon T., Christina S. Chao, Keith R. Anderson, Fernanda Kaufman, Christopher W. Johnson y Lori Sussel. "Nkx2.2 Activates the Ghrelin Promoter in Pancreatic Islet Cells". Molecular Endocrinology 24, n.º 2 (1 de febrero de 2010): 381–90. http://dx.doi.org/10.1210/me.2009-0360.

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Abstract Nkx2.2 is an essential regulator of pancreatic endocrine differentiation. Nkx2.2-null mice are completely devoid of β-ells and have a large reduction of α- and PP cells. In the place of these islet populations, there is a corresponding increase in the ghrelin-positive ε-cells. Molecular studies have indicated that Nkx2.2 functions as an activator and repressor to regulate islet cell fate decisions. To determine whether Nkx2.2 is solely important for islet cell fate decisions or also has the capability to control ghrelin at the promoter level, we studied the transcriptional regulation of the ghrelin promoter within the pancreas, in vitro and in vivo. These studies demonstrate that both of the previously identified transcriptional start sites in the ghrelin promoter are active within the embryonic pancreas; however, the long transcript is preferentially up-regulated in the Nkx2.2-null pancreas. We also show that the promoter region between −619 and −488 bp upstream of the translational start site is necessary for repression of ghrelin in αTC1 and βTC6 cells. Surprisingly, we also show that Nkx2.2 is able to bind to and activate the ghrelin promoter in several cell lines that do or do not express endogenous ghrelin. Together, these results suggest that the up-regulation of ghrelin expression in the Nkx2.2-null mice is not due to loss of repression of the ghrelin promoter in the nonghrelin islet populations. Furthermore, Nkx2.2 may contribute to the activation of ghrelin in mature islet ε-cells.

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Mariyath, Mubeena P. M., Mehdi H. Shahi, Shirin Farheen, Mohd Tayyab, Nabeela Khanam y Asif Ali. "Novel Homeodomain Transcription Factor Nkx2.2 in the Brain Tumor Development". Current Cancer Drug Targets 20, n.º 5 (5 de junio de 2020): 335–40. http://dx.doi.org/10.2174/1568009618666180102111539.

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Background: Complex central nervous system (CNS) is made up of neuronal cells and glial cells. Cells of central nervous system are able to regenerate after injury and during repairing. Sonic hedgehog pathway initiated by Shh-N a glycoprotein plays vital role in CNS patterning growth, development and now tumorigenesis. Nkx2.2 homeodomain transcription factor is an effecter molecule, which is positively regulated by Shh during normal growth. Nkx2.2 is essential for V3 domain specification during neural tube patterning at embryonic stage. MBP + oligodendrocytes are differentiated from progenitor cells which express Olig2. Nx2.2 is co-expressed with Olig2 in oligodendrocytes and is essential for later stage of oligodendrocyte maturation. Objective: This review paper explores the potential role of Nkx2.2 transcription factor in glioblastoma development. Conclusion: Shh pathway plays a vital role in oligodendrocytes differentiation and Nkx2.2 transcription factor is essential for oligodendrocytes differentiation and maturation. Intriguingly, down regulation of Nkx2.2 transcription factor with aberrant Shh signaling pathway is reported in glioma samples. So here it is suggested that Nkx2.2 expression pattern could be used as a potential biomarker for the early diagnosis of glioma.

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Tanaka, Makoto, Naohito Yamasaki y Seigo Izumo. "Phenotypic Characterization of the Murine Nkx2.6 Homeobox Gene by Gene Targeting". Molecular and Cellular Biology 20, n.º 8 (15 de abril de 2000): 2874–79. http://dx.doi.org/10.1128/mcb.20.8.2874-2879.2000.

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ABSTRACT The NK-2 homeobox genes have been shown to play critical roles in the development of specific organs and tissues. Nkx2.6 is a member of the NK-2 homeobox gene family and is most closely related to theDrosophila tinman gene. Nkx2.6 is expressed in the caudal pharyngeal pouches, the caudal heart progenitors, the sinus venosus, and the outflow tract of the heart and in a short segment of the gut at early stages of embryogenesis. To investigate the function of Nkx2.6 in vivo, we generated mice with null mutations of Nkx2.6 by the gene targeting technique. Homozygous Nkx2.6 mutant mice were viable and fertile. There were no obvious abnormalities in the caudal pharyngeal pouch derivatives (the thymus, parathyroid glands, and thyroid gland), heart, and gut. Expression of Nkx2.6 overlaps that of Nkx2.5 in the pharynx and heart and that of Nkx2.3 in the pharynx. Interestingly, in mutant embryos homozygous for Nkx2.6, Nkx2.5 expression extended to the lateral side of the pharynx, suggesting a compensatory function of Nkx2.5 in the mutant pharyngeal pouches.

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Markey, Fatu Badiane, Brigette Romero, Vijay Parashar y Mona Batish. "Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma". Cells 10, n.º 6 (24 de mayo de 2021): 1300. http://dx.doi.org/10.3390/cells10061300.

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Ewing’s sarcoma (ES) is caused by a chromosomal translocation leading to the formation of the fused EWSFLI1 gene, which codes for an aberrant transcription factor EWSFLI1. The transcriptional targets of EWSFLI1 have been viewed as promising and novel drug targets in the treatment of ES. One such target is six transmembrane epithelial antigen of the prostate 1 (STEAP1), a transmembrane protein that is upregulated by EWSFLI1 in ES. STEAP1 is a hallmark of tumor invasiveness and an indicator of tumor responsiveness to therapy. EWSFLI1 binds to the STEAP1 promoter region, but the mechanism of action by which it upregulates STEAP1 expression in ES is not entirely understood. Upon analysis of the STEAP1 promoter, we predicted two binding sites for NKX2.2, another crucial transcription factor involved in ES pathogenesis. We confirmed the interaction of NKX2.2 with the STEAP1 promoter using chromatin immunoprecipitation (ChIP) analysis. We used single-molecule RNA imaging, biochemical, and genetic studies to identify the novel role of NKX2.2 in regulating STEAP1 expression in ES. Our results show that NKX2.2 is a co-regulator of STEAP1 expression and functions by interacting with the STEAP1 promoter at sites proximal to the reported EWSFLI1 sites. The co-operative interaction of NKX2.2 with EWSFLI1 in regulating STEAP1 holds potential as a new target for therapeutic interventions for ES.

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Płoszaj, Tomasz, Karolina Antosik, Paulina Jakiel, Agnieszka Zmysłowska y Maciej Borowiec. "Screening for extremely rare pathogenic variants of monogenic diabetes using targeted panel sequencing". Endocrine 73, n.º 3 (21 de mayo de 2021): 752–57. http://dx.doi.org/10.1007/s12020-021-02753-7.

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Abstract Aims Maturity‐onset diabetes of the young (MODY) is one of the rare monogenic forms of diabetes. To date, about 12 genes in the scientific literature are closely related to the occurrence of the disease phenotype. However, there is still a high prevalence of undiagnosed cases of so-called MODY-X whose genetic background is still unknown. Methods We performed tNGS for 523 patients with suspected MODY. Next 357 selected patients, in whom no damaging variants were found in 12 major genes causing MODY, were screened for the presence of pathogenic variants in four candidate genes (MNX1, RFX6, NKX2.2, and NKX6.1). All data were generated in one tNGS sequencing reaction and confirmed by Sanger sequencing. Results In total, we selected five potentially damaging variants, in eight patients, in RFX6, NKX2.2, and NKX6.1 genes. Four of them have never been described in literature before. The frequency of occurrence of two of them in the RFX6 gene significantly differed in relation to the healthy population. The analysis of segregation in the family did not reveal that they were the only cause of the disease phenotype. Conclusions The very-rare variants indicated in this study show that this type of research on large population groups may help in the future for better understanding and more accurate diagnostics of extremely rare forms of MODY.

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Nevin, M., X. Song, S. Japoni, J. Zagozewski, Q. Jiang, O. Becher, R. Godbout, DA Underhill y DD Eisenstat. "09 Could DLX2 regulation of neural progenitor cell fate contribute to differentiation of diffuse intrinsic pontine glioma (DIPG)?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, S3 (junio de 2018): S16. http://dx.doi.org/10.1017/cjn.2018.305.

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Introduction: Diffuse intrinsic pontine glioma (DIPG) is refractory to therapy. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse loses tangential GABAergic interneuron migration to the neocortex. We have identified genes that encode glutamic acid decarboxylase (GAD) enzymes as direct targets of DLX1/DLX2. In DIPG patients with H3.3 K27M mutations there is decreased Dlx2 and increased expression of the myelin transcription factor, Myt1. Methods and Results: We used bioinformatics approaches and chromatin immunoprecipitation (ChIP) assays to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed. The functional consequences of Dlx2 co-expression with reporter constructs of ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of gene targets in vitro. qPCR showed increased Olig2 and Nkx2.2 expression in the DKO forebrain. Stable transfection of a murine DIPG cell line with Dlx2 resulted in increased Gad1 and Gad2 and decreased Olig2 and Nkx2.2 expression. Of significance, we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). Conclusions: DLX transcription factors promote GABAergic interneuron and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG provides a promising lead towards exploration of differentiation as a therapeutic strategy for DIPG.

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Schwitzgebel, V. M., D. W. Scheel, J. R. Conners, J. Kalamaras, J. E. Lee, D. J. Anderson, L. Sussel, J. D. Johnson y M. S. German. "Expression of neurogenin3 reveals an islet cell precursor population in the pancreas". Development 127, n.º 16 (15 de agosto de 2000): 3533–42. http://dx.doi.org/10.1242/dev.127.16.3533.

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Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors including the basic helix-loop-helix (bHLH) proteins. To delineate this cascade, we began by establishing the position of neurogenin3, a bHLH factor found in the pancreas during fetal development. We detect neurogenin3 immunoreactivity transiently in scattered ductal cells in the fetal mouse pancreas, peaking at embryonic day 15.5. Although not detected in cells expressing islet hormones or the islet transcription factors Isl1, Brn4, Pax6 or PDX1, neurogenin3 is detected along with early islet differentiation factors Nkx6.1 and Nkx2.2, establishing that it is expressed in immature cells in the islet lineage. Analysis of transcription factor-deficient mice demonstrates that neurogenin3 expression is not dependent on neuroD1/BETA2, Mash1, Nkx2.2, Nkx6.1, or Pax6. Furthermore, early expression of neurogenin3 under control of the Pdx1 promoter is alone sufficient to drive early and ectopic differentiation of islet cells, a capability shared by the pancreatic bHLH factor, neuroD1/BETA2, but not by the muscle bHLH factor, MyoD. However, the islet cells produced in these transgenic experiments are overwhelmingly (alpha) cells, suggesting that factors other than the bHLH factors are required to deviate from a default * cell fate. These data support a model in which neurogenin3 acts upstream of other islet differentiation factors, initiating the differentiation of endocrine cells, but switching off prior to final differentiation. The ability to uniquely identify islet cell precursors by neurogenin3 expression allows us to determine the position of other islet transcription factors in the differentiation cascade and to propose a map for the islet cell differentiation pathway.

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Anderson, Keith R. y Lori Sussel. "Nkx2.2 transcriptional targets important for islet differentiation". Developmental Biology 319, n.º 2 (julio de 2008): 573. http://dx.doi.org/10.1016/j.ydbio.2008.05.376.

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Tochitani, Shiro y Yoshihide Hayashizaki. "Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation". Biochemical and Biophysical Research Communications 372, n.º 4 (agosto de 2008): 691–96. http://dx.doi.org/10.1016/j.bbrc.2008.05.127.

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Soula, C., C. Danesin, P. Kan, M. Grob, C. Poncet y P. Cochard. "Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism". Development 128, n.º 8 (15 de abril de 2001): 1369–79. http://dx.doi.org/10.1242/dev.128.8.1369.

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In the vertebrate spinal cord, oligodendrocytes arise from the ventral part of the neuroepithelium, a region also known to generate somatic motoneurons. The emergence of oligodendrocytes, like that of motoneurons, depends on an inductive signal mediated by Sonic hedgehog. We have defined the precise timing of oligodendrocyte progenitor specification in the cervico-brachial spinal cord of the chick embryo. We show that ventral neuroepithelial explants, isolated at various development stages, are unable to generate oligodendrocytes in culture until E5 but become able to do so in an autonomous way from E5.5. This indicates that the induction of oligodendrocyte precursors is a late event that occurs between E5 and E5.5, precisely at the time when the ventral neuroepithelium stops producing somatic motoneurons. Analysis of the spatial restriction of oligodendrocyte progenitors, evidenced by their expression of O4 or PDGFR(α), indicate that they always lie within the most ventral Nkx2.2-expressing domain of the neuroepithelium, and not in the adjacent domain characterized by Pax6 expression from which somatic motoneurons emerge. We then confirm that Shh is necessary between E5 and E5.5 to specify oligodendrocyte precursors but is no longer required beyond this stage to maintain ongoing oligodendrocyte production. Furthermore, Shh is sufficient to induce oligodendrocyte formation from ventral neuroepithelial explants dissected at E5. Newly induced oligodendrocytes expressed Nkx2.2 but not Pax6, correlating with the in vivo observation. Altogether, our results show that, in the chick spinal cord, oligodendrocytes originate from Nkx2.2-expressing progenitors.

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Muraguchi, Teruyuki, Shingo Tanaka, Daisuke Yamada, Akira Tamase, Mitsutoshi Nakada, Hideo Nakamura, Takayuki Hoshii et al. "NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells". Cancer Research 71, n.º 3 (17 de diciembre de 2010): 1135–45. http://dx.doi.org/10.1158/0008-5472.can-10-2304.

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Nevin, Mikaela, Janine Gallego, Xiaohua Song, Qiang Jiang, Alan Underhill, Roseline Godbout, Oren Becher y David Eisenstat. "DIPG-43. CAN WE REPROGRAM DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)? EXPLORING THE ROLE OF DISTALLESS/DLX HOMEOBOX GENE REGULATION OF OLIGODENDROGLIAL PROGENITOR CELLS (OPC) IN THE DEVELOPING VERTEBRATE NERVOUS SYSTEM". Neuro-Oncology 22, Supplement_3 (1 de diciembre de 2020): iii295. http://dx.doi.org/10.1093/neuonc/noaa222.090.

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Abstract BACKGROUND The identification of H3.3/H3.1K27M in most DIPG has changed our understanding of this disease. H3K27M mutations usually demonstrate global loss of H3K27 trimethylation (me3) with gain of H3K27 acetylation (ac). Single cell RNAseq has identified the putative cell of origin as oligodendroglial progenitor cells (OPC). The distalless gene family is necessary for the differentiation and tangential migration of committed neural progenitors to become GABAergic interneurons. Dlx1/Dlx2 double knockout (DKO) cells from the ganglionic eminences (GE) transplanted into a wild-type environment become oligodendrocytes. RESULTS We identified DLX2 occupancy of early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo and confirmed direct DLX2 protein-promoter DNA binding in vitro. Co-expression of Dlx2 with target sequences reduced reporter gene expression in vitro. There was increased expression of OLIG2, NKX2.2 and PLP-1 expression in vivo, consistent with de-repression in the absence of Dlx1/Dlx2 function. Transient over-expression of a Dlx2-GFP construct into murine DIPG cells from a GEMM that develops DIPG resulted in significant increases in expression of Gad isoforms with concomitant decreases in Olig2 and Nkx2.2. Dlx2-transfected mDIPG cells also demonstrated reduced migration, invasion and colony formation in vitro. Of significance, there was global restoration of H3K27me3 with corresponding loss of H3K27ac expression in transfected cells compared to controls. CONCLUSIONS DLX2 promotes GABAergic differentiation and migration while concomitantly repressing OPC differentiation in vivo. Developmental reprogramming of mDIPG cells by DLX2 demonstrates the potential role for directed differentiation strategies towards improving patient outcomes for this devastating pediatric cancer.

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Holz, A., H. Kollmus, J. Ryge, V. Niederkofler, J. Dias, J. Ericson, E. T. Stoeckli, O. Kiehn y H. H. Arnold. "The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance". Development 137, n.º 24 (10 de noviembre de 2010): 4249–60. http://dx.doi.org/10.1242/dev.053819.

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22

Dubreuil, Véronique, Marie-Rose Hirsch, Caroline Jouve, Jean-François Brunet y Christo Goridis. "The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis". Development 129, n.º 22 (15 de noviembre de 2002): 5241–53. http://dx.doi.org/10.1242/dev.129.22.5241.

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Within the developing vertebrate nervous system, specific subclasses of neurons are produced in vastly different numbers at defined times and locations. This implies the concomitant activation of a program that controls pan-neuronal differentiation and of a program that specifies neuronal subtype identity, but how these programs are coordinated in time and space is not well understood. Our previous loss- and gain-of-function studies have defined Phox2b as a homeodomain transcription factor that coordinately regulates generic and type-specific neuronal properties. It is necessary and sufficient to impose differentiation towards a branchio- and viscero-motoneuronal phenotype and at the same time promotes generic neuronal differentiation. We have examined the underlying genetic interactions. We show thatPhox2b has a dual action on pan-neuronal differentiation. It upregulates the expression of proneural genes (Ngn2) when expressed alone and upregulates the expression of Mash1 when expressed in combination with Nkx2.2. By a separate pathway, Phox2brepresses expression of the inhibitors of neurogenesis Hes5 andId2. The role of Phox2b in the specification of neuronal subtype identity appears to depend in part on its capacity to act as a patterning gene in the progenitor domain. Phox2b misexpression represses the Pax6 and Olig2 genes, which should inhibit a branchiomotor fate, and induces Nkx6.1 and Nkx6.2, which are expressed in branchiomotor progenitors. We further show that Phox2b behaves like a transcriptional activator in the promotion of both, generic neuronal differentiation and expression of the motoneuronal marker Islet1. These results provide insights into the mechanisms by which a homeodomain transcription factor through interaction with other factors controls both generic and type-specific features of neuronal differentiation.

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Raum, Jeffrey C., Kevin Gerrish, Isabella Artner, Eva Henderson, Min Guo, Lori Sussel, Jonathan C. Schisler, Christopher B. Newgard y Roland Stein. "FoxA2, Nkx2.2, and PDX-1 Regulate Islet β-Cell-Specific mafA Expression through Conserved Sequences Located between Base Pairs −8118 and −7750 Upstream from the Transcription Start Site". Molecular and Cellular Biology 26, n.º 15 (1 de agosto de 2006): 5735–43. http://dx.doi.org/10.1128/mcb.00249-06.

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ABSTRACT The MafA transcription factor is both critical to islet β-cell function and has a unique pancreatic cell-type-specific expression pattern. To localize the potential transcriptional regulatory region(s) involved in directing expression to the β cell, areas of identity within the 5′ flanking region of the mouse, human, and rat mafA genes were found between nucleotides −9389 and −9194, −8426 and −8293, −8118 and −7750, −6622 and −6441, −6217 and −6031, and −250 and +56 relative to the transcription start site. The identity between species was greater than 75%, with the highest found between bp −8118 and −7750 (∼94%, termed region 3). Region 3 was the only upstream mammalian conserved region found in chicken mafA (88% identity). In addition, region 3 uniquely displayed β-cell-specific activity in cell-line-based reporter assays. Important regulators of β-cell formation and function, PDX-1, FoxA2, and Nkx2.2, were shown to specifically bind to region 3 in vivo using the chromatin immunoprecipitation assay. Mutational and functional analyses demonstrated that FoxA2 (bp −7943 to −7910), Nkx2.2 (bp −7771 to −7746), and PDX-1 (bp −8087 to −8063) mediated region 3 activation. Consistent with a role in transcription, small interfering RNA-mediated knockdown of PDX-1 led to decreased mafA mRNA production in INS-1-derived β-cell lines (832/13 and 832/3), while MafA expression was undetected in the pancreatic epithelium of Nkx2.2 null animals. These results suggest that β-cell-type-specific mafA transcription is principally controlled by region 3-acting transcription factors that are essential in the formation of functional β cells.

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Habener, Joel F., Daniel M. Kemp y Melissa K. Thomas. "Minireview: Transcriptional Regulation in Pancreatic Development". Endocrinology 146, n.º 3 (1 de marzo de 2005): 1025–34. http://dx.doi.org/10.1210/en.2004-1576.

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Considerable progress has been made in the understanding of the sequential activation of signal transduction pathways and the expression of transcription factors during pancreas development. Much of this understanding has been obtained by analyses of the phenotypes of mice in which the expression of key genes has been disrupted (knockout mice). Knockout of the genes for Pdx1, Hlxb9, Isl1, or Hex results in an arrest of pancreas development at a very early stage (embryonic d 8–9). Disruption of genes encoding components of the Notch signaling pathway, e.g. Hes1 or neurogenin-3, abrogates development of the endocrine pancreas (islets of Langerhans). Disruption of transcription factor genes expressed more downstream in the developmental cascade (Beta2/NeuroD, Pax4, NKx2.2, and Nkx6.1) curtails the formation of insulin-producing β-cells. An understanding of the importance of transcription factor genes during pancreas development has provided insights into the pathogenesis of diabetes, in which the mass of insulin-producing β-cells is reduced.

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25

Doyle, Michelle J. y Lori Sussel. "Nkx2.2 Regulates β-Cell Function in the Mature Islet". Diabetes 56, n.º 8 (24 de abril de 2007): 1999–2007. http://dx.doi.org/10.2337/db06-1766.

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Yoshida, Akihiko, Shigeki Sekine, Koji Tsuta, Masashi Fukayama, Koh Furuta y Hitoshi Tsuda. "NKX2.2 is a Useful Immunohistochemical Marker for Ewing Sarcoma". American Journal of Surgical Pathology 36, n.º 7 (julio de 2012): 993–99. http://dx.doi.org/10.1097/pas.0b013e31824ee43c.

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27

Mastracci, Teresa L., Chyuan-Sheng Lin y Lori Sussel. "Generation of mice encoding a conditional allele of Nkx2.2". Transgenic Research 22, n.º 5 (15 de marzo de 2013): 965–72. http://dx.doi.org/10.1007/s11248-013-9700-0.

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28

Nelson, Shelley B., Christoph Janiesch y Maike Sander. "Expression of Nkx6 Genes in the Hindbrain and Gut of the Developing Mouse". Journal of Histochemistry & Cytochemistry 53, n.º 6 (junio de 2005): 787–90. http://dx.doi.org/10.1369/jhc.5b6619.2005.

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The Nkx6 gene family of homeodomain transcription factors consists of three members. For two, Nkx6.1 and Nkx6.2, important developmental roles in the central nervous system and pancreas have been demonstrated. Here we introduce the third member of the Nkx6 gene family, Nkx6.3, and identify similar and distinct patterns of expression for all three Nkx6 genes in the hindbrain and gut of the developing mouse embryo.

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Takahashi, Masanori y Noriko Osumi. "Pax6 regulates specification of ventral neurone subtypes in the hindbrain by establishing progenitor domains". Development 129, n.º 6 (15 de marzo de 2002): 1327–38. http://dx.doi.org/10.1242/dev.129.6.1327.

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Recent studies have shown that generation of different kinds of neurones is controlled by combinatorial actions of homeodomain (HD) proteins expressed in the neuronal progenitors. Pax6 is a HD protein that has previously been shown to be involved in the differentiation of the hindbrain somatic (SM) motoneurones and V1 interneurones in the hindbrain and/or spinal cord. To investigate in greater depth the role of Pax6 in generation of the ventral neurones, we first examined the expression patterns of HD protein genes and subtype-specific neuronal markers in the hindbrain of the Pax6 homozygous mutant rat. We found that Islet2 (SM neurone marker) and En1 (V1 interneurone marker) were transiently expressed in a small number of cells, indicating that Pax6 is not directly required for specification of these neurones. We also observed that domains of all other HD protein genes (Nkx2.2, Nkx6.1, Irx3, Dbx2 and Dbx1) were shifted and their boundaries became blurred. Thus, Pax6 is required for establishment of the progenitor domains of the ventral neurones. Next, we performed Pax6 overexpression experiments by electroporating rat embryos in whole embryo culture. Pax6 overexpression in the wild type decreased expression of Nkx2.2, but ectopically increased expression of Irx3, Dbx1 and Dbx2. Moreover, electroporation of Pax6 into the Pax6 mutant hindbrain rescued the development of Islet2-positive and En1-positive neurones. To know reasons for perturbed progenitor domain formation in Pax6 mutant, we examined expression patterns of Shh signalling molecules and states of cell death and cell proliferation. Shh was similarly expressed in the floor plate of the mutant hindbrain, while the expressions of Ptc1, Gli1 and Gli2 were altered only in the progenitor domains for the motoneurones. The position and number of TUNEL-positive cells were unchanged in the Pax6 mutant. Although the proportion of cells that were BrdU-positive slightly increased in the mutant, there was no relationship with specific progenitor domains. Taken together, we conclude that Pax6 regulates specification of the ventral neurone subtypes by establishing the correct progenitor domains.

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Tanaka, Makoto, Martina Schinke, Hai-Sun Liao, Naohito Yamasaki y Seigo Izumo. "Nkx2.5 and Nkx2.6, Homologs ofDrosophila tinman, Are Required for Development of the Pharynx". Molecular and Cellular Biology 21, n.º 13 (1 de julio de 2001): 4391–98. http://dx.doi.org/10.1128/mcb.21.13.4391-4398.2001.

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ABSTRACT Nkx2.5 and Nkx2.6 are murine homologs of Drosophilatinman. Their genes are expressed in the ventral region of the pharynx at early stages of embryogenesis. However, no abnormalities in the pharynges of embryos with mutations in either Nkx2.5 or Nkx2.6 have been reported. To examine the function of Nkx2.5 and Nkx2.6 in the formation of the pharynx, we generated and analyzed Nkx2.5 and Nkx2.6 double-mutant mice. Interestingly, in the double-mutant embryos, the pharynx did not form properly. Pharyngeal endodermal cells were largely missing, and the mutant pharynx was markedly dilated. Moreover, we observed enhanced apoptosis and reduced proliferation in pharyngeal endodermal cells of the double-mutant embryos. These results demonstrated a critical role of the NK-2 homeobox genes in the differentiation, proliferation, and survival of pharyngeal endodermal cells. Furthermore, the development of the atrium was less advanced in the double-mutant embryos, indicating that these two genes are essential for both pharyngeal and cardiac development.

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Jarrar, Wassan, Jose M. Dias, Johan Ericson, Hans-Henning Arnold y Andreas Holz. "Nkx2.2 and Nkx2.9 Are the Key Regulators to Determine Cell Fate of Branchial and Visceral Motor Neurons in Caudal Hindbrain". PLOS ONE 10, n.º 4 (28 de abril de 2015): e0124408. http://dx.doi.org/10.1371/journal.pone.0124408.

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Gotoh, Hitoshi, Katsuhiko Ono, Tadashi Nomura, Hirohide Takebayashi, Hidekiyo Harada, Harukazu Nakamura y Kazuhiro Ikenaka. "Nkx2.2+ Progenitors Generate Somatic Motoneurons in the Chick Spinal Cord". PLoS ONE 7, n.º 12 (17 de diciembre de 2012): e51581. http://dx.doi.org/10.1371/journal.pone.0051581.

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Harrington, Jamie K., Robert Sorabella, Abigail Tercek, Joseph R. Isler y Kimara L. Targoff. "Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, n.º 3 (1 de septiembre de 2017): R265—R271. http://dx.doi.org/10.1152/ajpregu.00223.2016.

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Heart rate variability (HRV) has become an important clinical marker of cardiovascular health and a research measure for the study of the cardiac conduction system and its autonomic controls. While the zebrafish ( Danio rerio) is an ideal vertebrate model for understanding heart development, HRV has only recently been investigated in this system. We have previously demonstrated that nkx2.5 and nkx2.7, two homologues of Nkx2–5 expressed in zebrafish cardiomyocytes, play vital roles in maintaining cardiac chamber-specific characteristics. Given observed defects in ventricular and atrial chamber identities in nkx2.5−/− embryos coupled with conduction system abnormalities in murine models of Nkx2.5 insufficiency, we postulated that reduced HRV would serve as a marker of poor cardiac health in nkx2.5 mutants and in other zebrafish models of human congenital heart disease. Using live video image acquisition, we derived beat-to-beat intervals to compare HRV in wild-type and nkx2.5−/− embryos. Our data illustrate that the nkx2.5 loss-of-function model exhibits increased heart rate and decreased HRV when compared with wild type during embryogenesis. These findings validate HRV analysis as a useful quantitative tool for assessment of cardiac health in zebrafish and underscore the importance of nkx2.5 in maintaining normal heart rate and HRV during early conduction system development.

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Hessabi, Behnam, Ines Schmidt y Reinhard Walther. "The Homeodomain of Nkx2.2 Carries Two Cooperatively Acting Nuclear Localization Signals". Biochemical and Biophysical Research Communications 270, n.º 3 (abril de 2000): 695–700. http://dx.doi.org/10.1006/bbrc.2000.2491.

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Arnes, Luis, Kevin Leclerc, Jessica M. Friel, Susan B. Hipkens, Mark A. Magnuson y Lori Sussel. "Generation of Nkx2.2:lacZ mice using recombination-mediated cassette exchange technology". genesis 50, n.º 8 (19 de mayo de 2012): 612–24. http://dx.doi.org/10.1002/dvg.22037.

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Watanabe, Masahiko, Tarik Hadzic y Akiko Nishiyama. "Transient upregulation of Nkx2.2 expression in oligodendrocyte lineage cells during remyelination". Glia 46, n.º 3 (2004): 311–22. http://dx.doi.org/10.1002/glia.20006.

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Heddad Masson, Mounia, Caroline Poisson, Audrey Guérardel, Aline Mamin, Jacques Philippe y Yvan Gosmain. "Foxa1 and Foxa2 Regulate α-Cell Differentiation, Glucagon Biosynthesis, and Secretion". Endocrinology 155, n.º 10 (1 de octubre de 2014): 3781–92. http://dx.doi.org/10.1210/en.2013-1843.

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Abstract The Forkhead box A transcription factors are major regulators of glucose homeostasis. They show both distinct and redundant roles during pancreas development and in adult mouse β-cells. In vivo ablation studies have revealed critical implications of Foxa1 on glucagon biosynthesis and requirement of Foxa2 in α-cell terminal differentiation. In order to examine the respective role of these factors in mature α-cells, we used small interfering RNA (siRNA) directed against Foxa1 and Foxa2 in rat primary pancreatic α-cells and rodent α-cell lines leading to marked decreases in Foxa1 and Foxa2 mRNA levels and proteins. Both Foxa1 and Foxa2 control glucagon gene expression specifically through the G2 element. Although we found that Foxa2 controls the expression of the glucagon, MafB, Pou3f4, Pcsk2, Nkx2.2, Kir6.2, and Sur1 genes, Foxa1 only regulates glucagon gene expression. Interestingly, the Isl1 and Gipr genes were not controlled by either Foxa1 or Foxa2 alone but by their combination. Foxa1 and Foxa2 directly activate and bind the promoter region the Nkx2.2, Kir6.2 and Sur1, Gipr, Isl1, and Pou3f4 genes. We also demonstrated that glucagon secretion is affected by the combined effects of Foxa1 and Foxa2 but not by either one alone. Our results indicate that Foxa1 and Foxa2 control glucagon biosynthesis and secretion as well as α-cell differentiation with both common and unique target genes.

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Wang, Yu-cheng, Marlene B. Zuraek, Yasuhiro Kosaka, Yasuharu Ota, Michael S. German, Evan S. Deneris, Emily K. Bergsland, David B. Donner, Robert S. Warren y Eric K. Nakakura. "The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine". Endocrine-Related Cancer 17, n.º 1 (marzo de 2010): 283–91. http://dx.doi.org/10.1677/erc-09-0243.

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Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (−/−) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (−/−) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.

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Choi, Michael Y., Anthony I. Romer, Yang Wang, Melissa P. Wu, Susumu Ito, Andrew B. Leiter y Ramesh A. Shivdasani. "Requirement of the Tissue-Restricted Homeodomain Transcription Factor Nkx6.3 in Differentiation of Gastrin-Producing G Cells in the Stomach Antrum". Molecular and Cellular Biology 28, n.º 10 (17 de marzo de 2008): 3208–18. http://dx.doi.org/10.1128/mcb.01737-07.

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ABSTRACT Many homeodomain transcription factors function in organogenesis and cell differentiation. The Nkx family illustrates these functions especially well, and the Nkx6 subfamily controls differentiation in the central nervous system and pancreas. Nkx6.3, a recent addition to this subfamily, overlaps Nkx6.1 and Nkx6.2 in expression in the hindbrain and stomach. Nkx6.3 transcripts localize in the epithelium of the most distal stomach region, the antrum and pylorus; expression in the adult intestine is lower and confined to the proximal duodenum. Nkx6.3 − / − mice develop and grow normally, with a grossly intact stomach and duodenum. These mice show markedly reduced gastrin mRNA, many fewer gastrin-producing (G) cells in the stomach antrum, hypogastrinemia, and increased stomach luminal pH, with a corresponding increase in somatostatin mRNA levels and antral somatostatin-producing (D) cells. They express normal levels of other transcription factors required for gastric endocrine cell differentiation, Pdx1, Pax6, and Ngn3; conversely, Ngn3 − / − mice, which also show reduced gastrin levels, express Nkx6.3 normally. These studies implicate Nkx6.3 as a selective regulator of G- and D-cell lineages, which are believed to derive from a common progenitor, and suggest that it operates in parallel with Ngn3.

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Afrikanova, Ivka, Mayra Yebra, Megan Simpkinson, Yang Xu, Alberto Hayek y Anthony Montgomery. "Inhibitors of Src and Focal Adhesion Kinase Promote Endocrine Specification". Journal of Biological Chemistry 286, n.º 41 (18 de agosto de 2011): 36042–52. http://dx.doi.org/10.1074/jbc.m111.290825.

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Stepwise approaches for the derivation of β-cells from human embryonic stem cells have been described. However, low levels of endocrine specification limit the final yield of insulin-producing β-cells. In this study, we show that the pyrrolo-pyrimidine Src family kinase (SFK) inhibitor PP2 effectively promotes the endocrine specification of human embryonic stem cell derivatives based on its capacity to induce the expression of proendocrine transcription factors (NGN3, NEUROD1, NKX2.2, and PAX4) and to significantly increase the final yield of insulin-positive cells. We further demonstrate that PP2 inhibits the activation of focal adhesion kinase (FAK), and selective inhibition of this kinase is also sufficient to induce early endocrine commitment based on increased expression of NGN3, NEUROD1, and NKX2.2. Additional studies using dominant negative constructs and isolated human fetal pancreata suggest that c-Src is at least partially responsible for inhibiting early endocrine specification. Mechanistically, we propose that inhibition of SFK/FAK signaling can promote endocrine specification by limiting activation of the TGFβR/Smad2/3 pathway. Moreover, we show that inhibition of SFK/FAK signaling suppresses cell growth, increases the expression of the β-cell-associated cyclin-dependent kinase inhibitor p57kip2, and simultaneously suppresses the expression of Id1 and Id2. This study has important implications for the derivation of β-cells for the cell-based therapy of diabetes and sheds new light on the signaling events that regulate early endocrine specification.

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Heremans, Yves, Mark Van De Casteele, Peter in't Veld, Gerard Gradwohl, Palle Serup, Ole Madsen, Daniel Pipeleers y Harry Heimberg. "Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3". Journal of Cell Biology 159, n.º 2 (28 de octubre de 2002): 303–12. http://dx.doi.org/10.1083/jcb.200203074.

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Regulatory proteins have been identified in embryonic development of the endocrine pancreas. It is unknown whether these factors can also play a role in the formation of pancreatic endocrine cells from postnatal nonendocrine cells. The present study demonstrates that adult human pancreatic duct cells can be converted into insulin-expressing cells after ectopic, adenovirus-mediated expression of the class B basic helix-loop-helix factor neurogenin 3 (ngn3), which is a critical factor in embryogenesis of the mouse endocrine pancreas. Infection with adenovirus ngn3 (Adngn3) induced gene and/or protein expression of NeuroD/β2, Pax4, Nkx2.2, Pax6, and Nkx6.1, all known to be essential for β-cell differentiation in mouse embryos. Expression of ngn3 in adult human duct cells induced Notch ligands Dll1 and Dll4 and neuroendocrine- and β-cell–specific markers: it increased the percentage of synaptophysin- and insulin-positive cells 15-fold in ngn3-infected versus control cells. Infection with NeuroD/β2 (a downstream target of ngn3) induced similar effects. These data indicate that the Delta-Notch pathway, which controls embryonic development of the mouse endocrine pancreas, can also operate in adult human duct cells driving them to a neuroendocrine phenotype with the formation of insulin-expressing cells.

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Anderson, William J. y Vickie Y. Jo. "Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations". Diagnostics 11, n.º 4 (12 de abril de 2021): 690. http://dx.doi.org/10.3390/diagnostics11040690.

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The diagnosis of benign and malignant soft tissue and bone neoplasms is a challenging area of surgical pathology, due to the large number, rarity, and histologic diversity of tumor types. In recent years, diagnosis and classification has been aided substantially by our growing understanding of recurrent molecular alterations in these neoplasms. Concurrently, the role of diagnostic immunohistochemistry has also expanded, with the development of numerous biomarkers based on underlying molecular events. Such biomarkers allow us to infer the presence of these events and can therefore substitute for other ancillary molecular genetic techniques (e.g., fluorescence in situ hybridization, polymerase chain reaction, and next-generation sequencing). In this review, we discuss a range of biomarkers currently available for these neoplasms, highlighting the accuracy, staining characteristics, and interpretation pitfalls of each antibody. These include immunohistochemical antibodies that represent reliable surrogates for the detection of gene fusions (e.g., STAT6, CAMTA1, FOSB, DDIT3) and more recently described breakpoint-specific antibodies (e.g., SS18-SSX, PAX3/7-FOXO1). Additionally, discussed are markers that correlate with the presence of gene amplifications (e.g., MDM2, CDK4), deletions (e.g., SMARCB1, SMARCA4), single nucleotide variants (e.g., G34W, K36M), aberrant methylation (H3K27me3), and increased expression as discovered through gene expression profiling (e.g., MUC4, DOG1, ETV4, NKX2.2, NKX3.1).

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Zhou, Qiao, Gloria Choi y David J. Anderson. "The bHLH Transcription Factor Olig2 Promotes Oligodendrocyte Differentiation in Collaboration with Nkx2.2". Neuron 31, n.º 5 (septiembre de 2001): 791–807. http://dx.doi.org/10.1016/s0896-6273(01)00414-7.

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Gotoh, Hitoshi, Katsuhiko Ono, Hirohide Takebayashi, Hidekiyo Harada, Harukazu Nakamura y Kazuhiro Ikenaka. "Genetically-defined lineage tracing of Nkx2.2-expressing cells in chick spinal cord". Developmental Biology 349, n.º 2 (enero de 2011): 504–11. http://dx.doi.org/10.1016/j.ydbio.2010.10.007.

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Okahara, Kyohei, Yasuhiko Kizuka, Shinobu Kitazume, Fumi Ota, Kazuki Nakajima, Yoshio Hirabayashi, Motoko Maekawa, Takeo Yoshikawa y Naoyuki Taniguchi. "Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2". Glycobiology 24, n.º 10 (11 de mayo de 2014): 926–34. http://dx.doi.org/10.1093/glycob/cwu042.

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Papizan, J. B., R. A. Singer, S. I. Tschen, S. Dhawan, J. M. Friel, S. B. Hipkens, M. A. Magnuson, A. Bhushan y L. Sussel. "Nkx2.2 repressor complex regulates islet -cell specification and prevents -to- -cell reprogramming". Genes & Development 25, n.º 21 (1 de noviembre de 2011): 2291–305. http://dx.doi.org/10.1101/gad.173039.111.

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Xu, Sai y Ji-Ping Xu. "Present status and expectation of aristaless-related homeobox (ARX) in endocrine pancreas". International Journal of Developmental Biology 63, n.º 11-12 (2019): 579–87. http://dx.doi.org/10.1387/ijdb.190242sx.

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The aristaless-related homeobox (ARX) gene has become one of most frequently mutated genes which is closely linked with development of the vertebrate central nervous system; however, the molecular and clinical bases of its function in the proliferation and differentiation of the endocrine pancreas have not, to date, been systematically characterized. ARX is considered as a regulator which determines endocrine cell fate and a bio-marker of the pancreatic α-cell. Disruption and mutation of ARX are found to lead to the deletion and reduction of α-cells both in mice models and in humans. Furthermore, expression of ARX is regulated by multiple transcription factors involved in development of the pancreas, such as Ngn3, Isl1, Nkx2.2 and Nkx6.1. Taken together, given the vital importance of glucagon in diabetes treatment, it is possible that ARX may down-regulate exorbitant glucagon levels by reducing the number of α-cells as a direct target; thus, the role of ARX in the maintenance of α-cell identity and quantity should be investigated and summarized. This article mainly focuses on the role of ARX in the endocrine pancreas, introduces the ARX-related animal model and transcription factors, and highlights the latest advances in our understanding in order to provide a clearer theoretical foundation for future scientific research.

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Hoffman, Brad, Daniel Kok, Joy Witzsche, Martin Hirst, Gordon Robertson, Pamela A. Hoodless, Jones y Marco Marra. "Genome-wide analysis of Nkx2.2 binding sites using ChIP-tag sequencing (ChIP-TS)". Developmental Biology 306, n.º 1 (junio de 2007): 354. http://dx.doi.org/10.1016/j.ydbio.2007.03.226.

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49

Applequist, Joanna M., Mattias Karlen, Elisa Jordi, Thomas Perlmann y Johan Ericson. "Temporal patterning determines visceral motoneuron subtypes generated from Nkx2.2 + progenitors in the hindbrain". Developmental Biology 306, n.º 1 (junio de 2007): 430. http://dx.doi.org/10.1016/j.ydbio.2007.03.459.

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50

Desai, Shailey, Zoe Loomis, Aimee Pugh-Bernard, Jessica Schrunk, Michelle J. Doyle, Angela Minic, Erica McCoy y Lori Sussel. "Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine". Developmental Biology 313, n.º 1 (enero de 2008): 58–66. http://dx.doi.org/10.1016/j.ydbio.2007.09.047.

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