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

Featured publications

  1. 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)
  2. 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)
  3. 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)
  4. 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)
  5. 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)
  6. PIQ-ing into chromatin architecture. Rieck S, Wright C (2014) Nat Biotechnol 32(2): 138-40
    › Primary publication · 24509760 (PubMed)
  7. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H (2014) Nat Biotechnol 32(1): 76-83
    › Primary publication · 24240391 (PubMed) · PMC4096987 (PubMed Central)
  8. The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CC, Litingtung Y, Chiang C (2013) Dev Cell 27(3): 278-92
    › Primary publication · 24229643 (PubMed) · PMC3860749 (PubMed Central)
  9. Identification and manipulation of biliary metaplasia in pancreatic tumors. Delgiorno KE, Hall JC, Takeuchi KK, Pan FC, Halbrook CJ, Washington MK, Olive KP, Spence JR, Sipos B, Wright CV, Wells JM, Crawford HC (2014) Gastroenterology 146(1): 233-44.e5
    › Primary publication · 23999170 (PubMed) · PMC3870045 (PubMed Central)
  10. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Sugiyama T, Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK (2013) Proc Natl Acad Sci U S A 110(31): 12691-6
    › Primary publication · 23852729 (PubMed) · PMC3732989 (PubMed Central)