The Experts below are selected from a list of 1395 Experts worldwide ranked by ideXlab platform

Padma-sheila Jayaraman - One of the best experts on this subject based on the ideXlab platform.

  • leukemogenic mechanisms and targets of a nup98 HHEX fusion in acute myeloid leukemia
    Blood, 2008
    Co-Authors: Dragana Jankovic, Paolo Gorello, Roberta La Starza, Cecile Desjobert, Padma-sheila Jayaraman, Martin Brutsche, Florent Baty, Ting Liu, Sabine Ehret
    Abstract:

    We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.

Maurice A Canham - One of the best experts on this subject based on the ideXlab platform.

  • HHEX is a transcriptional regulator of the vegfc flt4 prox1 signaling axis during vascular development
    Nature Communications, 2018
    Co-Authors: Sebastien Gauvrit, Alethia Villasenor, Boris Strilic, Philip Kitchen, Michelle M Collins, Ruben Marinjuez, Stefan Guenther, Hansmartin Maischein, Nana Fukuda, Maurice A Canham
    Abstract:

    Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that HHEX is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.

Jinrong Peng - One of the best experts on this subject based on the ideXlab platform.

  • zebrafish HHEX null mutant develops an intrahepatic intestinal tube due to de repression of cdx1b and pdx1
    Journal of Molecular Cell Biology, 2019
    Co-Authors: Ce Gao, Weidong Huang, Yuqi Gao, Lingfei Luo, Honghui Huang, Jun Chen, Jinrong Peng
    Abstract:

    The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (HHEX) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish HHEX-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that HHEX binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that HHEX, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

  • zebrafish HHEX null mutant develops an intrahepatic intestinal tube due to de repression of cdx1b and pdx1
    bioRxiv, 2018
    Co-Authors: Ce Gao, Weidong Huang, Yuqi Gao, Lingfei Luo, Honghui Huang, Jun Chen, Jinrong Peng
    Abstract:

    The hepatopancreatic duct (HPD) system links liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder and pancreatic duct. Haematopoietically expressed homeobox (HHEX) protein plays an essential role in the establishment of HPD, however, the molecular mechanism remains elusive. Here we show that zebrafish HHEX-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fabp2a. Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 were expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 restored the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis shows that HHEX binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that HHEX, Cdx1b and Pdx1 form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

Clifford W. Bogue - One of the best experts on this subject based on the ideXlab platform.

  • Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of HHEX in Mice
    2016
    Co-Authors: Mark J. Ferreira, Clifford W. Bogue, Lindsay B. Mckenna, Jia Zhang, Maximilian Reichert, Basil Bakir, Elizabeth L. Buza, Emma E. Furth, Anil K. Rustgi, Klaus H
    Abstract:

    BACKGROUND & AIMS—Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (HHEX) in ductal secretion and pancreatitis. METHODS—We derived mice with pancreas-specific, Cremediated HHEX gene ablation to determine the requirement of HHEX in the pancreatic duct in early life and in adult stages. Histologic and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells were isolated to discover differentially expressed transcripts upon acute HHEX ablation on a cell autonomous level. RESULTS—HHEX protein was detected throughout the embryonic and adult ductal trees. Ablation of HHEX in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. HHEX ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbation of expression of Hnf6, Hnf1β, or th

  • Acute myeloid leukemia requires HHEX to enable PRC2-mediated epigenetic repression of Cdkn2a
    Genes & development, 2016
    Co-Authors: Benjamin J. Shields, Jacob T. Jackson, Donald Metcalf, Wei Shi, Qiutong Huang, Alexandra L. Garnham, Stefan P Glaser, Dominik Beck, John E. Pimanda, Clifford W. Bogue
    Abstract:

    Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene HHEX is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for HHEX for leukemic growth. Loss of HHEX leads to expression of the Cdkn2a-encoded tumor suppressors p16(INK4a) and p19(ARF), which are required for growth arrest and myeloid differentiation following HHEX deletion. Mechanistically, we show that HHEX binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, HHEX is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.

  • Differentiation of VEGFR2+ Hepatic Endoderm.
    2016
    Co-Authors: Adam S. Arterbery, Clifford W. Bogue
    Abstract:

    HHEX-/- DE cells did not differentiate into VEGFR2+ early hepatic progenitor cells. A) Analysis of FACS for ALB and VEGFR2 revealed that only HHEX+/+ (blue) cultures produced significant populations of HE progenitor cells and the majority of ALB+ cells were also VEGFR2+ in HHEX+/+ cultures. IGG plot confirms antigen specificity. B and C) Single channel and merged immunofluorescence staining of HHEX+/+ ALB+/VEGFR2+ sorted cells that were replated for 24 hours in HE media. Sorted cells showed co-expression of ALB and VEGFR2 (B), and were absent for the expression of the hematopoietic/endothelial marker CD34 (C). (Scale bars = 10μM.) D and E) Single channel and merged immunofluorescence staining of HHEX+/+ and HHEX-/- ALB+/VEGFR2+ sorted cells that were replated for 7 days in HE media. Despite rapid expansion of the HHEX-/- sorted cells, only HHEX+/+ sorted cells showed a co-expression of ALB and AAT that is indicative of further/continued hepatic differentiation. (Scale bars = 50μM.) F) Normalized mRNA expression of hepatic and Vegf signaling gene markers in ALB+/VEGFR2+ sorted cells from both HHEX+/+ and HHEX-/- cultures. HHEX-/- sorted cells show heavily attenuated mRNA expression for hepatic genes and no significant reduction in Vegfa expression when compared to cells from the previous DE differentiation stage. (*p

  • HHEX Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling
    2016
    Co-Authors: Adam S. Arterbery, Clifford W. Bogue
    Abstract:

    Elucidating the molecular mechanisms involved in the differentiation of stem cells to hepatic cells is critical for both understanding normal developmental processes as well as for optimizing the generation of functional hepatic cells for therapy. We performed in vitro differentiation of mouse embryonic stem cells (mESCs) with a null mutation in the homeobox gene HHEX and show that HHEX-/- mESCs fail to differentiate from definitive endoderm (Sox17+/Foxa2+) to hepatic endoderm (Alb+/Dlk+). In addition, hepatic culture elicited a >7-fold increase in Vegfa mRNA expression in HHEX-/- cells compared to HHEX+/+ cells. Furthermore, we identified VEGFR2+/ALB+/CD34- in early HHEX+/+ hepatic cultures. These cells were absent in HHEX-/- cultures. Finally, through manipulation of HHEX and Vegfa expression, gain and loss of expression experiments revealed that HHEX shares an inverse relationship with the activity of the Vegf signaling pathway in supporting hepatic differentiation. In summary, our results suggest that HHEX represses Vegf signaling during hepatic differentiation of mouse ESCs allowing for cell-type autonomous regulation of Vegfr2 activity independent of endothelial cells.

  • Genotype Comparison using QPCR at each Differentiation Stage.
    2016
    Co-Authors: Adam S. Arterbery, Clifford W. Bogue
    Abstract:

    HHEX-/- HE cells did not show mRNA expression consistent with hepatic differentiation. A-E) Comparison of fold-change in normalized mRNA gene expression using differentiation-stage specific markers. Comparison of pluripotency gene markers reveal HHEX-/- (red) cells showed increased pluripotency relative to HHEX+/+ (blue) at each differentiation stage, particularly during HE differentiation (A, B, and E). Comparison of definitive endodermal gene markers reveal HHEX-/- cells fail to exhibit significant decreases in definitive endodermal gene expression characteristic of HE differentiation (C), and as seen in HHEX+/+ HE cells. HHEX+/+ HE cells showed dramatic increase in hepatic gene expression (D), while HHEX-/- cells showed a heavily attenuated expression. Comparison of Vegf signaling gene markers showed that HHEX-/- cells exhibit increased levels of ligands (Vegf-a) and receptor (Vegfr1 and Vegfr2) gene expression at each differentiation stage, but particularly during HE differentiation (A, B, and C). (Note raw data is presented in S1 Fig) (*p

Shinichi Aizawa - One of the best experts on this subject based on the ideXlab platform.

  • ave protein expression and visceral endoderm cell behavior during anterior posterior axis formation in mouse embryos asymmetry in otx2 and dkk1 expression
    Developmental Biology, 2015
    Co-Authors: Hideharu Hoshino, Go Shioi, Shinichi Aizawa
    Abstract:

    The initial landmark of anterior-posterior (A-P) axis formation in mouse embryos is the distal visceral endoderm, DVE, which expresses a series of anterior genes at embryonic day 5.5 (E5.5). Subsequently, DVE cells move to the future anterior region, generating anterior visceral endoderm (AVE). Questions remain regarding how the DVE is formed and how the direction of the movement is determined. This study compares the detailed expression patterns of OTX2, HHEX, CER1, LEFTY1 and DKK1 by immunohistology and live imaging at E4.5-E6.5. At E6.5, the AVE is subdivided into four domains: most anterior (OTX2, HHEX, CER1-low/DKK1-high), anterior (OTX2, HHEX, CER1-high/DKK1-low), main (OTX2, HHEX, CER1, LEFTY1-high) and antero-lateral and posterior (OTX2, HHEX-low). The study demonstrates how this pattern is established. AVE protein expression in the DVE occurs de novo at E5.25-E5.5. Neither HHEX, LEFTY1 nor CER1 expression is asymmetric. In contrast, OTX2 expression is tilted on the future posterior side with the DKK1 expression at its proximal domain; the DVE cells move in the opposite direction of the tilt.