Profile

Vertebrate embryos form from initially symmetric fertilized eggs as a result of progressively more complex interactions between differently programmed groups of daughter cells that arise from the cleavage of the zygote. We are studying secreted intercellular signaling molecules or transcription factors that dictate cell fates in different parts of the embryo. These include the TGF -superfamily members nodal and BMP4 (and their transmembrane kinase receptors), and homeodomain-containing transcription factors, which are expressed according to the type of extracellular signals received by a cell. Our main model systems are the frog and mouse. Frog embryos can be microinjected with plasmids, mRNA, proteins and antibodies, and the large number of embryos available allows biochemical studies. In contrast, the mouse allows genetic analysis of function. We can transgenically misexpress proteins, or genes can be inactivated or mutated by gene recombination in ES cells. The latter can be done globally, or tissue-specifically, by inactivation techniques that can be targeted to chosen tissues and switched on/off as required. Proof of the power of these strategies comes from our finding that inactivating the pdx-1 homeobox gene completely prevents the formation of the pancreas; similar defects have been found in newborn humans with pdx-1 mutations. Furthermore, PDX-1 is probably an essential transcriptional regulator of the insulin gene, and/or other genes involved in cell function in the Islets of Langerhans of the adult pancreas. We are determining the cis-elements activating pdx-1 in the embryonic pancreas and adult endocrine cells, studying endocrine/exocrine lineage pathways, and determining the precise role of pdx-1 and other transcriptional regulators such as the bHLH factor Ptf1a in pancreas formation, function and insulin expression. We are specifically interested in identifying pancreatic stem cells and finding ways to convert embryonic or adult stem cells (which may come from the bone marrow, nervous system, or from within the pancreas itself) into pancreatic tissue, ultimately for transplantation therapy of diabetes.

We have recently found evidence that the expression of Ptf1a dictates an organ choice of endodermal stem cells between duodenal and pancreatic fates. These studies involved nactivating Ptf1a in mouse, together with lineage tracing techniques for following cells after inactivation. Different vertebrates have variable numbers of nodal-related genes, which encode intercellular signaling molecules that induce profound alterations in cell fate or behaviours such as migration. A particularly exciting discovery made a few years ago was that a frog nodal-related gene, Xnr-1, is expressed only on the embryo's left side, where it acts to specify a "left-right" asymmetry involved in the formation of the stereotypical and required internal asymmetric anatomy of the heart, vascular system, and viscera. We are mapping the cis-acting sequences controlling Xnr-1 expression to characterize the factors activating its expression in these fascinating patterns, and investigating the extracellular regulation of this cell-cell signaling molecule. In addition, our finding that the classical zebrafish mutant, cyclops, corresponds to a lesion in a nodal-related gene has introduced new concepts regarding the timing and players involved in establishing precursors of the floor plate, an organizing tissue located ventrally in the neural tube that is required for normal CNS patterning. Our long-term goal is to provide insight into the molecular mechanisms responsible for the coordinated development of complex organ systems, with deep relevance to human congenital birth defects.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis. Sánchez-Arévalo Lobo VJ, Fernández LC, Carrillo-de-Santa-Pau E, Richart L, Cobo I, Cendrowski J, Moreno U, Del Pozo N, Megías D, Bréant B, Wright CV, Magnuson M, Real FX (2017) Gut
    › Primary publication · 28159836 (PubMed)
  2. PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. Roy N, Takeuchi KK, Ruggeri JM, Bailey P, Chang D, Li J, Leonhardt L, Puri S, Hoffman MT, Gao S, Halbrook CJ, Song Y, Ljungman M, Malik S, Wright CV, Dawson DW, Biankin AV, Hebrok M, Crawford HC (2016) Genes Dev 30(24): 2669-2683
    › Primary publication · 28087712 (PubMed) · PMC5238727 (PubMed Central)
  3. The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation. Yang YP, Magnuson MA, Stein R, Wright CV (2016) Development
    › Primary publication · 27993987 (PubMed)
  4. New ideas connecting the cell cycle and pancreatic endocrine-lineage specification. Bechard ME, Wright CV (2016) Cell Cycle
    › Primary publication · 27860540 (PubMed)
  5. Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A. Hoang CQ, Hale MA, Azevedo-Pouly AC, Elsässer HP, Deering TG, Willet SG, Pan FC, Magnuson MA, Wright CV, Swift GH, MacDonald RJ (2016) Mol Cell Biol 36(24): 3033-3047
    › Primary publication · 27697859 (PubMed) · PMC5126291 (PubMed Central)
  6. Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells. Bechard ME, Bankaitis ED, Hipkens SB, Ustione A, Piston DW, Yang YP, Magnuson MA, Wright CV (2016) Genes Dev 30(16): 1852-65
    › Primary publication · 27585590 (PubMed) · PMC5024683 (PubMed Central)
  7. Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function. Henley KD, Stanescu DE, Kropp PA, Wright CV, Won KJ, Stoffers DA, Gannon M (2016) Cell Rep 15(12): 2637-50
    › Primary publication · 27292642 (PubMed) · PMC4917419 (PubMed Central)
  8. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Aoki R, Shoshkes-Carmel M, Gao N, Shin S, May CL, Golson ML, Zahm AM, Ray M, Wiser CL, Wright CV, Kaestner KH (2016) Cell Mol Gastroenterol Hepatol 2(2): 175-188
    › Primary publication · 26949732 (PubMed) · PMC4772878 (PubMed Central)
  9. Diabetes Caused by Elastase-Cre-Mediated Pdx1 Inactivation in Mice. Kodama S, Nakano Y, Hirata K, Furuyama K, Horiguchi M, Kuhara T, Masui T, Kawaguchi M, Gannon M, Wright CV, Uemoto S, Kawaguchi Y (2016) Sci Rep : 21211
    › Primary publication · 26887806 (PubMed) · PMC4758062 (PubMed Central)
  10. Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells. Pan FC, Brissova M, Powers AC, Pfaff S, Wright CV (2015) Development 142(21): 3637-48
    › Primary publication · 26534984 (PubMed) · PMC4647212 (PubMed Central)
  11. Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche. Bankaitis ED, Bechard ME, Wright CV (2015) Genes Dev 29(20): 2203-16
    › Primary publication · 26494792 (PubMed) · PMC4617982 (PubMed Central)
  12. Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3. Comer JD, Pan FC, Willet SG, Haldipur P, Millen KJ, Wright CV, Kaltschmidt JA (2015) Front Neural Circuits : 36
    › Primary publication · 26257608 (PubMed) · PMC4511845 (PubMed Central)
  13. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC (2015) Elife
    › Primary publication · 26151762 (PubMed) · PMC4536747 (PubMed Central)
  14. PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells. Teo AK, Tsuneyoshi N, Hoon S, Tan EK, Stanton LW, Wright CV, Dunn NR (2015) Stem Cell Reports 4(4): 578-90
    › Primary publication · 25843046 (PubMed) · PMC4400640 (PubMed Central)
  15. Disrupting Foxh1-Groucho interaction reveals robustness of nodal-based embryonic patterning. Halstead AM, Wright CV (2015) Mech Dev : 155-65
    › Primary publication · 25511461 (PubMed) · PMC4747026 (PubMed Central)
  16. Dominant and context-specific control of endodermal organ allocation by Ptf1a. Willet SG, Hale MA, Grapin-Botton A, Magnuson MA, MacDonald RJ, Wright CV (2014) Development 141(22): 4385-94
    › Primary publication · 25371369 (PubMed) · PMC4302917 (PubMed Central)
  17. Partial duct ligation: β-cell proliferation and beyond. Van de Casteele M, Leuckx G, Cai Y, Yuchi Y, Coppens V, De Groef S, Van Gassen N, Baeyens L, Heremans Y, Wright CV, Heimberg H (2014) Diabetes 63(8): 2567-77
    › Primary publication · 25060885 (PubMed)
  18. Symmetry breakage in the vertebrate embryo: when does it happen and how does it work? Blum M, Schweickert A, Vick P, Wright CV, Danilchik MV (2014) Dev Biol 393(1): 109-23
    › Primary publication · 24972089 (PubMed) · PMC4481729 (PubMed Central)
  19. Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding. Reinert RB, Cai Q, Hong JY, Plank JL, Aamodt K, Prasad N, Aramandla R, Dai C, Levy SE, Pozzi A, Labosky PA, Wright CV, Brissova M, Powers AC (2014) Development 141(7): 1480-91
    › Primary publication · 24574008 (PubMed) · PMC3957372 (PubMed Central)
  20. Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S, Fujiyama T, Yamada M, Chapman H, Campbell K, Magnuson MA, Wright CV, Kawaguchi Y, Ikenaka K, Takebayashi H, Ishiwata S, Ono Y, Hoshino M (2014) Nat Commun : 3337
    › Primary publication · 24535035 (PubMed)
  21. PIQ-ing into chromatin architecture. Rieck S, Wright C (2014) Nat Biotechnol 32(2): 138-40
    › Primary publication · 24509760 (PubMed)
  22. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. von Figura G, Morris JP, Wright CV, Hebrok M (2014) Gut 63(4): 656-64
    › Primary publication · 23645620 (PubMed) · PMC3883808 (PubMed Central)
  23. The evaluation of sexual harassment litigants: reducing discrepancies in the diagnosis of posttraumatic stress disorder. Lawson AK, Wright CV, Fitzgerald LF (2013) Law Hum Behav 37(5): 337-47
    › Primary publication · 23544390 (PubMed)
  24. Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. Liu J, Willet SG, Bankaitis ED, Xu Y, Wright CV, Gu G (2013) Genesis 51(6): 436-42
    › Primary publication · 23441020 (PubMed) · PMC3696028 (PubMed Central)
  25. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. 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 (2012) Cancer Cell 22(6): 737-50
    › Primary publication · 23201164 (PubMed) · PMC3568632 (PubMed Central)
  26. Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Kopinke D, Brailsford M, Pan FC, Magnuson MA, Wright CV, Murtaugh LC (2012) Dev Biol 362(1): 57-64
    › Primary publication · 22146645 (PubMed) · PMC3254730 (PubMed Central)
  27. Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism. Ahnfelt-Rønne J, Jørgensen MC, Klinck R, Jensen JN, Füchtbauer EM, Deering T, MacDonald RJ, Wright CV, Madsen OD, Serup P (2012) Development 139(1): 33-45
    › Primary publication · 22096075 (PubMed) · PMC3231770 (PubMed Central)
  28. Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie B, Tada M, Mohri D, Miyabayashi K, Asaoka Y, Maeda S, Ikenoue T, Tateishi K, Wright CV, Koike K, Omata M, Moses HL (2011) J Clin Invest 121(10): 4106-17
    › Primary publication · 21926469 (PubMed) · PMC3195452 (PubMed Central)
  29. A recombinase-mediated cassette exchange-derived cyan fluorescent protein reporter allele for Pdx1. Potter LA, Choi E, Hipkens SB, Wright CV, Magnuson MA (2012) Genesis 50(4): 384-92
    › Primary publication · 21913313 (PubMed) · PMC3870909 (PubMed Central)
  30. Context-specific α- to-β-cell reprogramming by forced Pdx1 expression. Yang YP, Thorel F, Boyer DF, Herrera PL, Wright CV (2011) Genes Dev 25(16): 1680-5
    › Primary publication · 21852533 (PubMed) · PMC3165933 (PubMed Central)
  31. Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers. Dorrell C, Grompe MT, Pan FC, Zhong Y, Canaday PS, Shultz LD, Greiner DL, Wright CV, Streeter PR, Grompe M (2011) Mol Cell Endocrinol 339(1-2): 144-50
    › Primary publication · 21539888 (PubMed) · PMC3112273 (PubMed Central)
  32. Rapid differential transport of Nodal and Lefty on sulfated proteoglycan-rich extracellular matrix regulates left-right asymmetry in Xenopus. Marjoram L, Wright C (2011) Development 138(3): 475-85
    › Primary publication · 21205792 (PubMed) · PMC3014634 (PubMed Central)
  33. Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas. Wang S, Yan J, Anderson DA, Xu Y, Kanal MC, Cao Z, Wright CV, Gu G (2010) Dev Biol 339(1): 26-37
    › Primary publication · 20025861 (PubMed) · PMC2824035 (PubMed Central)
  34. Stringent specificity in the construction of a GABAergic presynaptic inhibitory circuit. Betley JN, Wright CV, Kawaguchi Y, Erdélyi F, Szabó G, Jessell TM, Kaltschmidt JA (2009) Cell 139(1): 161-74
    › Primary publication · 19804761 (PubMed) · PMC2812434 (PubMed Central)
  35. Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3. Anderson KR, Torres CA, Solomon K, Becker TC, Newgard CB, Wright CV, Hagman J, Sussel L (2009) J Biol Chem 284(45): 31236-48
    › Primary publication · 19759004 (PubMed) · PMC2781522 (PubMed Central)