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    Matthias Hebrok, PhD

    TitleProfessor
    SchoolUCSF School of Medicine
    DepartmentDiabetes Center
    Address513 Parnassus Ave
    San Francisco CA 94143
    Phone415-514-0820
      Other Positions
      TitleDirector, Diabetes Center


       Overview 
       Overview
      The main focus of my lab is to understand how islets of Langerhans, the endocrine component of the pancreas, are formed during organogenesis, how their function is regulated in the mature organism, and how changes in gene expression might allow islet regeneration. Islet cells, including glucagon-producing a- and insulin-producing ß-cells, regulate blood glucose homeostasis. The importance of the latter is highlighted by the fact that loss of ß-cells leads to type I diabetes mellitus. Conventional treatment of diabetic patients is based on insulin injections. Unfortunately, episodes of hypo- and hyperglycemia occur frequently and result in severe secondary complications, including coronary and microvascular diseases. Recent reports have shown that islet transplantation successfully restores glucose tolerance. However islets are in short supply, a dilemma that severely restricts the feasibility of large-scale therapy through islet transplantation. An alternative approach is the regeneration of ß- or islet cells from committed precursor cells and the majority of the projects in my lab are designed to unravel the program that directs an ordinary cell in the gut to become a ß-cell. Understanding of these processes will be crucial for future cell replacement strategies.

      Analysis of known signaling pathways: We employ knockout and transgenic mice lines to study the effect of known signaling pathways involved in cell proliferation, differentiation and migration on islet progenitor cells. In particular, we are interested in understanding how components of the Hedgehog and Wnt pathways influence pancreas development and endocrine cell differentiation. While previous studies have suggested an inhibitory role for members of the Hedgehog family, our recent results indicate that some Hedgehog signaling is required for pancreas formation. Currently, we are using a combination of knockout and transgenic approaches to determine if manipulations of the Hedgehog and Wnt pathways stimulate ß-cell development and function.

      Identification of novel pancreas/islet genes: In another set of experiments we have identified novel pancreatic genes via 'gene-trapping'. This technique allows to randomly trap and mark genes by inserting a target construct containing the bacterial LacZ gene into the DNA of embryonic stem (ES) cells. Trapped genes are identified by sequencing of amplified cDNA fragments (5' RACE) and mouse lines are established by blastocyst injection. The insertion of the gene-trap vector places the bacterial ß-galactosidase gene under control of the promoter of the trapped gene. Thus, the normal expression pattern of this gene can rapidly be visualized by staining for ß-galactosidase activity within any given tissue, including the pancreas. More importantly, vector insertion causes either null or severe hypomorphic mutations that reveal if the trapped gene is essential for pancreas and ß-cell differentiation. These studies are done in collaboration with Marc Tessier-Lavigne, Stanford University, who is interested in brain development and is generously providing mice for our analysis.

      Generation of ß-cells from adult progenitor cells: Recent studies have shown that adult organ stem cells have the ability to develop into a number of different tissues. We are taking advantage of our understanding of pancreas development and have started to investigate if adult progenitor cells have the potential to develop into insulin-producing ß-cells. Bone marrow derived stem cells are co-cultured with embryonic pancreas buds that develop into endocrine islets and thus provide the necessary signals for ß-cell differentiation. Initially, we focus on murine adult stem cells, but will include human cells as soon as the 'proof of principle' experiments have shown that murine cells can adopt pancreatic fates.

      Model systems for pancreatic cancer: Overt hedgehog signaling has been implicated in cancer formation in various tissues; however it has not been linked to the formation of pancreatic adenocarcinomas, an aggressive form of cancer that is virtually incurable. We have started collaboration with Martin McMahon's laboratory at the UCSF Cancer Center to show that deregulated Hedgehog signaling promotes proliferation of pancreatic cancer cell lines and if inhibition of Hedgehog signaling blocks cell proliferation. Currently, we are manipulating the Hedgehog pathway in pancreatic tissue of transgenic animals to address the tumorigenic activity of this pathway in vivo.


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       Bibliographic 
       Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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      1. Folias AE, Penaranda C, Su AL, Bluestone JA, Hebrok M. Aberrant Innate Immune Activation following Tissue Injury Impairs Pancreatic Regeneration. PLoS One. 2014; 9(7):e102125.
        View in: PubMed
      2. Morris JP, Greer R, Russ HA, von Figura G, Kim GE, Busch A, Lee J, Hertel KJ, Kim S, McManus M, Hebrok M. Dicer Regulates Differentiation and Viability during Mouse Pancreatic Cancer Initiation. PLoS One. 2014; 9(5):e95486.
        View in: PubMed
      3. Folias AE, Hebrok M. Diabetes: Solving human ß-cell development-what does the mouse say? Nat Rev Endocrinol. 2014 May; 10(5):253-5.
        View in: PubMed
      4. von Figura G, Fukuda A, Roy N, Liku ME, Morris Iv JP, Kim GE, Russ HA, Firpo MA, Mulvihill SJ, Dawson DW, Ferrer J, Mueller WF, Busch A, Hertel KJ, Hebrok M. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat Cell Biol. 2014 Mar; 16(3):255-67.
        View in: PubMed
      5. Li K, Zhu S, Russ HA, Xu S, Xu T, Zhang Y, Ma T, Hebrok M, Ding S. Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell. 2014 Feb 6; 14(2):228-36.
        View in: PubMed
      6. Puri S, Akiyama H, Hebrok M. VHL-mediated disruption of Sox9 activity compromises ß-cell identity and results in diabetes mellitus. Genes Dev. 2013 Dec 1; 27(23):2563-75.
        View in: PubMed
      7. Puri S, García-Núñez A, Hebrok M, Cano DA. Elimination of von Hippel-Lindau function perturbs pancreas endocrine homeostasis in mice. PLoS One. 2013; 8(8):e72213.
        View in: PubMed
      8. Greer RL, Staley BK, Liou A, Hebrok M. Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar-to-ductal metaplasia. Gastroenterology. 2013 Nov; 145(5):1088-1097.e8.
        View in: PubMed
      9. Zhang Y, Morris JP, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M, Pasca di Magliano M. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 2013 Aug 1; 73(15):4909-22.
        View in: PubMed
      10. Stanger BZ, Hebrok M. Control of cell identity in pancreas development and regeneration. Gastroenterology. 2013 Jun; 144(6):1170-9.
        View in: PubMed
      11. Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, Anderson MS, Hebrok M. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 2013 Aug 1; 13(2):219-29.
        View in: PubMed
      12. von Figura G, Morris JP, Wright CV, Hebrok M. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut. 2014 Apr; 63(4):656-64.
        View in: PubMed
      13. Lin WC, Rajbhandari N, Liu C, Sakamoto K, Zhang Q, Triplett AA, Batra SK, Opavsky R, Felsher DW, DiMaio DJ, Hollingsworth MA, Morris JP, Hebrok M, Witkiewicz AK, Brody JR, Rui H, Wagner KU. Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Res. 2013 Mar 15; 73(6):1821-30.
        View in: PubMed
      14. Guo T, Landsman L, Li N, Hebrok M. Factors expressed by murine embryonic pancreatic mesenchyme enhance generation of insulin-producing cells from hESCs. Diabetes. 2013 May; 62(5):1581-92.
        View in: PubMed
      15. Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP, Pan FC, Akiyama H, Wright CV, Jensen K, Hebrok M, Sander M. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 Dec 11; 22(6):737-50.
        View in: PubMed
      16. Pasca di Magliano M, Forsmark C, Freedman S, Hebrok M, Pasricha PJ, Saluja A, Stanger BZ, Holt J, Serrano J, James SP, Rustgi AK. Advances in acute and chronic pancreatitis: from development to inflammation and repair. Gastroenterology. 2013 Jan; 144(1):e1-4.
        View in: PubMed
      17. Puri S, Hebrok M. Diabetic ß Cells: To Be or Not To Be? Cell. 2012 Sep 14; 150(6):1103-4.
        View in: PubMed
      18. Hebrok M. Generating ß cells from stem cells-the story so far. Cold Spring Harb Perspect Med. 2012 Jun; 2(6):a007674.
        View in: PubMed
      19. Fukuda A, Morris JP, Hebrok M. Bmi1 is required for regeneration of the exocrine pancreas in mice. Gastroenterology. 2012 Sep; 143(3):821-31.e1-2.
        View in: PubMed
      20. Qin H, Blaschke K, Wei G, Ohi Y, Blouin L, Qi Z, Yu J, Yeh RF, Hebrok M, Ramalho-Santos M. Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming. Hum Mol Genet. 2012 May 1; 21(9):2054-67.
        View in: PubMed
      21. Landsman L, Parent A, Hebrok M. Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice. Proc Natl Acad Sci U S A. 2011 Oct 11; 108(41):17010-5.
        View in: PubMed
      22. Landsman L, Nijagal A, Whitchurch TJ, Vanderlaan RL, Zimmer WE, Mackenzie TC, Hebrok M. Pancreatic mesenchyme regulates epithelial organogenesis throughout development. PLoS Biol. 2011 Sep; 9(9):e1001143.
        View in: PubMed
      23. Atkinson MA, Bluestone JA, Eisenbarth GS, Hebrok M, Herold KC, Accili D, Pietropaolo M, Arvan PR, Von Herrath M, Markel DS, Rhodes CJ. How does type 1 diabetes develop?: the notion of homicide or ß-cell suicide revisited. Diabetes. 2011 May; 60(5):1370-9.
        View in: PubMed
      24. Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ, Yu J, Hebrok M, Hochedlinger K, Costello JF, Song JS, Ramalho-Santos M. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol. 2011 May; 13(5):541-9.
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      25. Fukuda A, Wang SC, Morris JP, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011 Apr 12; 19(4):441-55.
        View in: PubMed
      26. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010 Oct; 10(10):683-95.
        View in: PubMed
      27. Kockel L, Kerr KS, Melnick M, Brückner K, Hebrok M, Perrimon N. Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling. PLoS Genet. 2010 Jun; 6(6):e1000990.
        View in: PubMed
      28. Cervantes S, Lau J, Cano DA, Borromeo-Austin C, Hebrok M. Primary cilia regulate Gli/Hedgehog activation in pancreas. Proc Natl Acad Sci U S A. 2010 Jun 1; 107(22):10109-14.
        View in: PubMed
      29. Puri S, Hebrok M. Cellular plasticity within the pancreas--lessons learned from development. Dev Cell. 2010 Mar 16; 18(3):342-56.
        View in: PubMed
      30. Lau J, Hebrok M. Hedgehog signaling in pancreas epithelium regulates embryonic organ formation and adult beta-cell function. Diabetes. 2010 May; 59(5):1211-21.
        View in: PubMed
      31. Morris JP, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest. 2010 Feb; 120(2):508-20.
        View in: PubMed
      32. Morris JP, Hebrok M. It's a free for all--insulin-positive cells join the group of potential progenitors for pancreatic ductal adenocarcinoma. Cancer Cell. 2009 Nov 6; 16(5):359-61.
        View in: PubMed
      33. Sekine S, Ogawa R, Mcmanus MT, Kanai Y, Hebrok M. Dicer is required for proper liver zonation. J Pathol. 2009 Nov; 219(3):365-72.
        View in: PubMed
      34. Guo T, Hebrok M. Stem cells to pancreatic beta-cells: new sources for diabetes cell therapy. Endocr Rev. 2009 May; 30(3):214-27.
        View in: PubMed
      35. Sekine S, Ogawa R, Ito R, Hiraoka N, McManus MT, Kanai Y, Hebrok M. Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis. Gastroenterology. 2009 Jun; 136(7):2304-2315.e1-4.
        View in: PubMed
      36. Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernández-Zapico ME, Hanahan D. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009 Jan 1; 23(1):24-36.
        View in: PubMed
      37. Cervantes S, Yamaguchi TP, Hebrok M. Wnt5a is essential for intestinal elongation in mice. Dev Biol. 2009 Feb 15; 326(2):285-94.
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      38. Puri S, Cano DA, Hebrok M. A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes. 2009 Feb; 58(2):433-41.
        View in: PubMed
      39. Cano DA, Hebrok M. Hedgehog spikes pancreas regeneration. Gastroenterology. 2008 Aug; 135(2):347-51.
        View in: PubMed
      40. Heiser PW, Cano DA, Landsman L, Kim GE, Kench JG, Klimstra DS, Taketo MM, Biankin AV, Hebrok M. Stabilization of beta-catenin induces pancreas tumor formation. Gastroenterology. 2008 Oct; 135(4):1288-300.
        View in: PubMed
      41. Bluestone JA, Hebrok M. Safer, longer-lasting regulatory T cells with beta-catenin. Nat Med. 2008 Feb; 14(2):118-9.
        View in: PubMed
      42. Cano DA, Rulifson IC, Heiser PW, Swigart LB, Pelengaris S, German M, Evan GI, Bluestone JA, Hebrok M. Regulated beta-cell regeneration in the adult mouse pancreas. Diabetes. 2008 Apr; 57(4):958-66.
        View in: PubMed
      43. Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, Scanlan TS, Hebrok M, Coughlin SR. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest. 2007 Dec; 117(12):4034-43.
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      44. Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T, Segara D, Dawson AC, Kench JG, Henshall SM, Sutherland RL, Dlugosz A, Rustgi AK, Hebrok M. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One. 2007; 2(11):e1155.
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      45. Burris RE, Hebrok M. Pancreatic innervation in mouse development and beta-cell regeneration. Neuroscience. 2007 Dec 12; 150(3):592-602.
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      46. Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One. 2007; 2(4):e392.
        View in: PubMed
      47. Robbins DJ, Hebrok M. Hedgehogs: la dolce vita. Workshop on Hedgehog-Gli Signaling in Cancer and Stem Cells. EMBO Rep. 2007 May; 8(5):451-5.
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      48. Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A. 2007 Apr 10; 104(15):6247-52.
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      49. Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007 Mar 20; 104(12):5103-8.
        View in: PubMed
      50. Puri S, Hebrok M. Dynamics of embryonic pancreas development using real-time imaging. Dev Biol. 2007 Jun 1; 306(1):82-93.
        View in: PubMed
      51. Sekine S, Gutiérrez PJ, Lan BY, Feng S, Hebrok M. Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy. Hepatology. 2007 Feb; 45(2):361-8.
        View in: PubMed
      52. Cano DA, Hebrok M, Zenker M. Pancreatic development and disease. Gastroenterology. 2007 Feb; 132(2):745-62.
        View in: PubMed
      53. Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 2006 Nov 15; 20(22):3161-73.
        View in: PubMed
      54. Cano DA, Sekine S, Hebrok M. Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology. 2006 Dec; 131(6):1856-69.
        View in: PubMed
      55. Heiser PW, Lau J, Taketo MM, Herrera PL, Hebrok M. Stabilization of beta-catenin impacts pancreas growth. Development. 2006 May; 133(10):2023-32.
        View in: PubMed
      56. Sekine S, Lan BY, Bedolli M, Feng S, Hebrok M. Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice. Hepatology. 2006 Apr; 43(4):817-25.
        View in: PubMed
      57. Lau J, Kawahira H, Hebrok M. Hedgehog signaling in pancreas development and disease. Cell Mol Life Sci. 2006 Mar; 63(6):642-52.
        View in: PubMed
      58. Kawahira H, Scheel DW, Smith SB, German MS, Hebrok M. Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev Biol. 2005 Apr 1; 280(1):111-21.
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      59. Perez SE, Cano DA, Dao-Pick T, Rougier JP, Werb Z, Hebrok M. Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo. Diabetes. 2005 Mar; 54(3):694-701.
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      60. Cano DA, Murcia NS, Pazour GJ, Hebrok M. Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development. 2004 Jul; 131(14):3457-67.
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      61. Hebrok M, Reichardt LF. Brain meets pancreas: netrin, an axon guidance molecule, controls epithelial cell migration. Trends Cell Biol. 2004 Apr; 14(4):153-5.
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      62. Heiser PW, Hebrok M. Development and cancer: lessons learned in the pancreas. Cell Cycle. 2004 Mar; 3(3):270-2.
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      63. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003 Dec; 3(12):903-11.
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      64. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003 Oct 23; 425(6960):851-6.
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      65. Kawahira H, Ma NH, Tzanakakis ES, McMahon AP, Chuang PT, Hebrok M. Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development. 2003 Oct; 130(20):4871-9.
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      66. Hebrok M. Hedgehog signaling in pancreas development. Mech Dev. 2003 Jan; 120(1):45-57.
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      67. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev. 2001 Jan 15; 15(2):111-27.
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      68. Hebrok M, Kim SK, St Jacques B, McMahon AP, Melton DA. Regulation of pancreas development by hedgehog signaling. Development. 2000 Nov; 127(22):4905-13.
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      69. Kim SK, Hebrok M, Li E, Oh SP, Schrewe H, Harmon EB, Lee JS, Melton DA. Activin receptor patterning of foregut organogenesis. Genes Dev. 2000 Aug 1; 14(15):1866-71.
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      70. Hebrok M, Kim SK, Melton DA. Screening for novel pancreatic genes expressed during embryogenesis. Diabetes. 1999 Aug; 48(8):1550-6.
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      71. Hebrok M, Kim SK, Melton DA. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 1998 Jun 1; 12(11):1705-13.
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      72. Kim SK, Hebrok M, Melton DA. Notochord to endoderm signaling is required for pancreas development. Development. 1997 Nov; 124(21):4243-52.
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      73. Hebrok M, Füchtbauer A, Füchtbauer EM. Repression of muscle-specific gene activation by the murine Twist protein. Exp Cell Res. 1997 May 1; 232(2):295-303.
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      74. Kim SK, Hebrok M, Melton DA. Pancreas development in the chick embryo. Cold Spring Harb Symp Quant Biol. 1997; 62:377-83.
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      75. Rohwedel J, Horák V, Hebrok M, Füchtbauer EM, Wobus AM. M-twist expression inhibits mouse embryonic stem cell-derived myogenic differentiation in vitro. Exp Cell Res. 1995 Sep; 220(1):92-100.
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      76. Hebrok M, Wertz K, Füchtbauer EM. M-twist is an inhibitor of muscle differentiation. Dev Biol. 1994 Oct; 165(2):537-44.
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