Identification of embryonic pancreatic genes using Xenopus DNA microarrays

The pancreas is both an exocrine and endocrine endodermal organ involved in digestion and glucose homeostasis. During embryogenesis, the anlagen of the pancreas arise from dorsal and ventral evaginations of the foregut that later fuse to form a single organ. To better understand the molecular genetics of early pancreas development, we sought to isolate markers that are uniquely expressed in this tissue. Microarray analysis was performed comparing dissected pancreatic buds, liver buds, and the stomach region of tadpole stage Xenopus embryos. A total of 912 genes were found to be differentially expressed between these organs during early stages of organogenesis. K‐means clustering analysis predicted 120 of these genes to be specifically enriched in the pancreas. Of these, we report on the novel expression patterns of 24 genes. Our analyses implicate the involvement of previously unsuspected signaling pathways during early pancreas development. Developmental Dynamics 238:1455–1466, 2009. © 2009 Wiley‐Liss, Inc.

[1]  R. Scheller,et al.  Amisyn, a Novel Syntaxin-binding Protein That May Regulate SNARE Complex Assembly* , 2002, The Journal of Biological Chemistry.

[2]  T. Voeltzel,et al.  Relationships of the Antiproliferative Proteins BTG1 and BTG2 with CAF1, the Human Homolog of a Component of the Yeast CCR4 Transcriptional Complex , 2001, The Journal of Biological Chemistry.

[3]  Yu-Chung Yang,et al.  Cited2 is required for normal hematopoiesis in the murine fetal liver. , 2007, Blood.

[4]  H. Edlund,et al.  Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. , 2005, Diabetes.

[5]  Ken W. Y. Cho,et al.  Identification of neural genes using Xenopus DNA microarrays , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[6]  R. Burgoyne,et al.  Amisyn Regulates Exocytosis and Fusion Pore Stability by Both Syntaxin-dependent and Syntaxin-independent Mechanisms* , 2005, Journal of Biological Chemistry.

[7]  M. Whitman,et al.  Timing of endogenous activin-like signals and regional specification of the Xenopus embryo. , 2001, Development.

[8]  M. Asashima,et al.  Screening for novel pancreatic genes from in vitro‐induced pancreas in Xenopus , 2003, Development, growth & differentiation.

[9]  K. Herrup,et al.  The essential role of Cited2, a negative regulator for HIF-1α, in heart development and neurulation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Melton,et al.  Regulation of pancreas development by hedgehog signaling. , 2000, Development.

[11]  C. Wylie,et al.  Maternal VegT is the initiator of a molecular network specifying endoderm in Xenopus laevis. , 2001, Development.

[12]  J. Slack,et al.  Development of the gut in Xenopus laevis , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[13]  A. Lukashin,et al.  Kirrel2, a novel immunoglobulin superfamily gene expressed primarily in beta cells of the pancreatic islets. , 2003, Genomics.

[14]  E. Lam,et al.  Cited2, a coactivator of HNF4alpha, is essential for liver development. , 2007, EMBO Journal.

[15]  J. Degen,et al.  Replacement by a lacZ reporter gene assigns mouse connexin36, 45 and 43 to distinct cell types in pancreatic islets. , 2004, Experimental cell research.

[16]  Bruce Aronow,et al.  Global expression analysis of gene regulatory pathways during endocrine pancreatic development , 2004, Development.

[17]  D. Melton,et al.  Single-cell transcript analysis of pancreas development. , 2003, Developmental cell.

[18]  L. Sussel,et al.  Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. , 2000, Development.

[19]  A. McMahon,et al.  FGFR-4, a new member of the fibroblast growth factor receptor family, expressed in the definitive endoderm and skeletal muscle lineages of the mouse. , 1991, Development.

[20]  C. Wright,et al.  The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors , 2002, Nature Genetics.

[21]  T. Pieler,et al.  Retinoic acid-mediated patterning of the pre-pancreatic endoderm in Xenopus operates via direct and indirect mechanisms , 2007, Mechanisms of Development.

[22]  S. Pfaff,et al.  Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice , 1999, Nature Genetics.

[23]  D. Melton,et al.  β-Catenin is essential for pancreatic acinar but not islet development , 2005, Development.

[24]  B. Hogan,et al.  PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. , 1996, Development.

[25]  A. Hayek,et al.  ICA69 is expressed equally in the human endocrine and exocrine pancreas , 1996, Diabetologia.

[26]  R. Scharfmann,et al.  Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Lu,et al.  Wnt 7 b Activates Canonical Signaling in Epithelial and Vascular Smooth Muscle Cells through Interactions with Fzd 1 , Fzd 10 , and LRP 5 , 2005 .

[28]  G. Rousseau,et al.  An endothelial-mesenchymal relay pathway regulates early phases of pancreas development. , 2006, Developmental biology.

[29]  C. Wylie,et al.  The role of Mixer in patterning the early Xenopus embryo , 2004, Development.

[30]  R. Patient,et al.  A role for GATA5 in Xenopus endoderm specification. , 2000, Development.

[31]  Jian Zhang,et al.  The Role of Maternal VegT in Establishing the Primary Germ Layers in Xenopus Embryos , 1998, Cell.

[32]  B. Habermann,et al.  Islet Cell Autoantigen of 69 kDa Is an Arfaptin-related Protein Associated with the Golgi Complex of Insulinoma INS-1 Cells* , 2003, Journal of Biological Chemistry.

[33]  A. Zorn,et al.  Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. , 2004, Development.

[34]  P. Serup,et al.  Expression and misexpression of members of the FGF and TGFβ families of growth factors in the developing mouse pancreas , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[35]  T. Mohun,et al.  Induction of cardiomyocytes by GATA4 in Xenopus ectodermal explants , 2003, Development.

[36]  P. Chambon,et al.  TIF1δ, a Novel HP1-interacting Member of the Transcriptional Intermediary Factor 1 (TIF1) Family Expressed by Elongating Spermatids* , 2004, Journal of Biological Chemistry.

[37]  V. Prince,et al.  Retinoids signal directly to zebrafish endoderm to specify insulin-expressing β-cells , 2006, Development.

[38]  M. Ffrench,et al.  BTG1, a member of a new family of antiproliferative genes. , 1992, The EMBO journal.

[39]  S. D. Fraser,et al.  Semaphorin-plexin signaling guides patterning of the developing vasculature. , 2004, Developmental cell.

[40]  R. Lahesmaa,et al.  Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets , 2005, Diabetologia.

[41]  T. Muramatsu,et al.  Midkine and pleiotrophin in neural development and cancer. , 2004, Cancer letters.

[42]  David J. Anderson,et al.  Notch signalling controls pancreatic cell differentiation , 1999, Nature.

[43]  Ken W. Y. Cho,et al.  Xenopus as a model system to study transcriptional regulatory networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  H. Edlund,et al.  The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. , 1996, Development.

[45]  J. Thiery,et al.  Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. , 2001, Development.

[46]  Olivier Pourquié,et al.  Retinoic acid , 2008, Current Biology.

[47]  V. Prince,et al.  Retinoic Acid Signaling Is Required for a Critical Early Step in Zebrafish Pancreatic Development , 2002, Current Biology.

[48]  S. Leach,et al.  Wnt/β-catenin signaling is required for development of the exocrine pancreas , 2007, BMC Developmental Biology.

[49]  Joseph A. Martial,et al.  Reciprocal endoderm-mesoderm interactions mediated by fgf24 and fgf10 govern pancreas development , 2007, Development.

[50]  T. Schlange,et al.  Expression analysis of the chicken homologue of CITED2 during early stages of embryonic development , 2000, Mechanisms of Development.

[51]  T. Pieler,et al.  Pancreatic protein disulfide isomerase (XPDIp) is an early marker for the exocrine lineage of the developing pancreas in Xenopus laevis embryos. , 2004, Gene expression patterns : GEP.

[52]  Ken W. Y. Cho,et al.  Xenopus cDNA microarray identification of genes with endodermal organ expression , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[53]  V. Schwitzgebel Programming of the pancreas , 2001, Molecular and Cellular Endocrinology.

[54]  R. Beddington,et al.  Msg1 and Mrg1, founding members of a gene family, show distinct patterns of gene expression during mouse embryogenesis , 1998, Mechanisms of Development.

[55]  C. Niehrs,et al.  Synexpression groups in eukaryotes , 1999, Nature.

[56]  S. Takao,et al.  Increased Midkine Gene Expression in Human Gastrointestinal Cancers , 1995, Japanese journal of cancer research : Gann.

[57]  R. Harland,et al.  In situ hybridization: an improved whole-mount method for Xenopus embryos. , 1991, Methods in cell biology.

[58]  D. Melton,et al.  Development of the pancreas in Xenopus laevis , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[59]  A. Zorn,et al.  Sox17 and β-catenin cooperate to regulate the transcription of endodermal genes , 2004 .

[60]  Klaus H. Kaestner,et al.  The initiation of liver development is dependent on Foxa transcription factors , 2005, Nature.

[61]  Harumi Saito,et al.  RTP Family Members Induce Functional Expression of Mammalian Odorant Receptors , 2004, Cell.

[62]  Xueying Gu,et al.  Wnt signaling regulates pancreatic beta cell proliferation. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[63]  R. Huang,et al.  A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embryogenesis , 1990, The Journal of cell biology.

[64]  P. Carmeliet,et al.  Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene ngn3 , 2000, Molecular and Cellular Biology.

[65]  N. Colburn,et al.  Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Yutaka Seino,et al.  Cblb is a major susceptibility gene for rat type 1 diabetes mellitus , 2002, Nature Genetics.

[67]  M. Lu,et al.  Wnt7b Activates Canonical Signaling in Epithelial and Vascular Smooth Muscle Cells through Interactions with Fzd1, Fzd10, and LRP5 , 2005, Molecular and Cellular Biology.

[68]  J. Paré,et al.  The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element* , 2004, Journal of Biological Chemistry.

[69]  D. Stephens,et al.  PCTAIRE protein kinases interact directly with the COPII complex and modulate secretory cargo transport , 2005, Journal of Cell Science.

[70]  George,et al.  Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen. , 1993, The Journal of clinical investigation.

[71]  H. Nishina,et al.  Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b , 2000, Nature.

[72]  D. Melton,et al.  Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[73]  T. Shioda,et al.  Cited1 and Cited2 are differentially expressed in the developing kidney but are not required for nephrogenesis , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[74]  D. Stainier A glimpse into the molecular entrails of endoderm formation. , 2002, Genes & development.

[75]  Ryoichiro Kageyama,et al.  Control of endodermal endocrine development by Hes-1 , 2000, Nature Genetics.

[76]  T. Pieler,et al.  Retinoic acid signaling is essential for pancreas development and promotes endocrine at the expense of exocrine cell differentiation in Xenopus. , 2004, Developmental biology.

[77]  R. Nusse,et al.  Wnt signaling regulates pancreatic β cell proliferation , 2007, Proceedings of the National Academy of Sciences.

[78]  M. Horb,et al.  Germ layers to organs: using Xenopus to study "later" development. , 2006, Seminars in cell & developmental biology.

[79]  J. Auwerx,et al.  Pancreatic-Duodenal Homeobox 1 Regulates Expression of Liver Receptor Homolog 1 during Pancreas Development , 2003, Molecular and Cellular Biology.

[80]  F. Casas,et al.  Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation , 2005, Oncogene.

[81]  D. Melton,et al.  Genes, signals, and lineages in pancreas development. , 2003, Annual review of cell and developmental biology.

[82]  Ken W. Y. Cho,et al.  TGF-beta signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis. , 2007, Genes & development.

[83]  D. Melton,et al.  Notochord repression of endodermal Sonic hedgehog permits pancreas development. , 1998, Genes & development.

[84]  V. Prince,et al.  A conserved role for retinoid signaling in vertebrate pancreas development , 2004, Development Genes and Evolution.

[85]  F. Wardle,et al.  Transcriptional regulation of mesendoderm formation in Xenopus. , 2006, Seminars in cell & developmental biology.

[86]  W. Wahli,et al.  FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis , 1994, Molecular and cellular biology.

[87]  P. Concannon,et al.  Polymorphic variation in the CBLB gene in human type 1 diabetes , 2004, Genes and Immunity.

[88]  Johan Auwerx,et al.  Liver Receptor Homolog 1 Controls the Expression of Carboxyl Ester Lipase* , 2003, Journal of Biological Chemistry.

[89]  Y. Yuzawa,et al.  Growth factor midkine is involved in the pathogenesis of diabetic nephropathy. , 2006, The American journal of pathology.

[90]  S. Arber,et al.  Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9 , 1999, Nature Genetics.

[91]  D. Melton,et al.  Notochord to endoderm signaling is required for pancreas development. , 1997, Development.

[92]  Edwin Liu,et al.  Type 1 diabetes: recent developments , 2004, BMJ : British Medical Journal.

[93]  M. Okada,et al.  PCTAIRE 2, a Cdc2-related serine/threonine kinase, is predominantly expressed in terminally differentiated neurons. , 1997, European journal of biochemistry.

[94]  J. Huelsken,et al.  Pancreas-Specific Deletion of β-Catenin Reveals Wnt-Dependent and Wnt-Independent Functions during Development , 2005, Current Biology.

[95]  S. Dunwoodie,et al.  Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development , 2005, Development.

[96]  P. Chambon,et al.  Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. , 2005, Developmental biology.

[97]  Hironori Katoh,et al.  Direct Interaction of Rnd1 with Plexin-B1 Regulates PDZ-RhoGEF-mediated Rho Activation by Plexin-B1 and Induces Cell Contraction in COS-7 Cells* , 2003, Journal of Biological Chemistry.

[98]  K. Willecke,et al.  Defective vascular development in connexin 45-deficient mice. , 2000, Development.

[99]  E. Lam,et al.  Cited2, a coactivator of HNF4α, is essential for liver development , 2007 .

[100]  M. Pietropaolo Islet cell autoantigen 69 kDa (ICA69) , 1996 .

[101]  A. Hasilik,et al.  Pdcd4 inhibits growth of tumor cells by suppression of carbonic anhydrase type II , 2004, Molecular and Cellular Endocrinology.

[102]  Seung K. Kim,et al.  Signaling and transcriptional control of pancreatic organogenesis. , 2002, Current opinion in genetics & development.

[103]  E. Shevach,et al.  Cbl-b regulates the CD28 dependence of T-cell activation , 2000, Nature.