NEURAL TUBE DEFECTS

Summary

Principal Investigator: D R McClay
Abstract: DESCRIPTION (Provided by applicant): Neural tube defects (NTDs) occur in about 1/1000 births in the United States. Though much has been learned from these defects, and folate treatment has significantly reduced their occurrence, much remains to be learned. It has been estimated that perhaps 50% or more of all NTDs have a genetic cause though the genes responsible generally are not known. There is thought to be an influence of environmental effects on those genetic deficits, but at what level is not known. This program project will use several models to examine these questions with the goal of increasing knowledge of the genetic component of NTDs. The project brings together six investigators at Duke University who will work collaboratively on this problem. The six projects include: (1) John Klingensmith, who will study the basis of fully-penetrant NTD phenotypes in mice mutant for the BMP antagonist noggin. He will misexpress mutant BMP receptors via the Cre/lox system to determine how BMP signaling controls dorsal development. (2) Erik Meyers who will follow preliminary loss of function studies indicating that a balance between the BMP and Fgf signaling families is required for normal neural tube patterning and closure. Cre/loxP analysis will ectopically localize either increased expression or decreased expression of these components as a test of function. (3) David McClay who will examine quantitative adhesion changes during normal neural tube closure and compare those data with homozygotes having a fully penetrant NTD and heterozygotes with no visible abnormal phenotype. The hypothesis is that the heterozygotes will nevertheless have a measurable deficit in adhesion. (4) Dan Kiehart who will study dpp mutants (the BMP homolog in flies) that cause a failure in dorsal closure. This process has many cellular morphogenetic properties that are similar to neural tube closure in mammals. He will screen for mutants in a search for genes whose products are required for TGFbeta signaling function including cellular aspects of morphogenesis. (5) Elwood Linney who will use a new promoter trap retroviral vector that his laboratory constructed to identify and isolate genes expressed during neural tube development in zebrafish. (6) Marcy Speer, who, based on the other components of this PO1, will examine the hereditary factors predisposing humans to NTDs, with the ultimate aim of characterizing interactions between genes and between genes and the environment, eventually leading to mechanisms for the prevention of these frequent birth defects.
Funding Period: 2001-09-01 - 2007-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Expression of cyp26b1 during zebrafish early development
    Qingshun Zhao
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Gene Expr Patterns 5:363-9. 2005
  2. pmc High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35
    Demetra S Stamm
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Birth Defects Res A Clin Mol Teratol 76:499-505. 2006
  3. ncbi BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites
    Shigeto Miura
    Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, MD C4 10, C458, Research Triangle Park, NC 27709, USA
    Development 133:3767-75. 2006
  4. pmc Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions
    Abee L Boyles
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Environ Health Perspect 114:1547-52. 2006
  5. pmc Protein tyrosine and serine-threonine phosphatases in the sea urchin, Strongylocentrotus purpuratus: identification and potential functions
    C A Byrum
    Developmental, Cell, and Molecular Biology Group, Box 91000, Duke University, Durham, NC 27708, USA
    Dev Biol 300:194-218. 2006
  6. pmc The genome of the sea urchin Strongylocentrotus purpuratus
    Erica Sodergren
    Science 314:941-52. 2006
  7. ncbi The bone morphogenetic protein antagonist noggin regulates mammalian cardiac morphogenesis
    Murim Choi
    Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
    Circ Res 100:220-8. 2007
  8. pmc Cordon-bleu is an actin nucleation factor and controls neuronal morphology
    Rashmi Ahuja
    Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
    Cell 131:337-50. 2007
  9. ncbi Refinement of 2q and 7p loci in a large multiplex NTD family
    Demetra S Stamm
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Birth Defects Res A Clin Mol Teratol 82:441-52. 2008
  10. pmc 3.6 kb genomic sequence from Takifugu capable of promoting axon growth-associated gene expression in developing and regenerating zebrafish neurons
    Ava J Udvadia
    University of Wisconsin Milwaukee, Department of Biological Sciences, Great Lakes WATER Institute UWM GLWI, 600 E Greenfield Avenue, Milwaukee, WI 53204, United States
    Gene Expr Patterns 8:382-8. 2008

Scientific Experts

  • Qingshun Zhao
  • C A Byrum
  • Ava J Udvadia
  • John Klingensmith
  • Marcy C Speer
  • John R Gilbert
  • Timothy M George
  • Abee L Boyles
  • Demetra S Stamm
  • Murim Choi
  • Rolf W Stottmann
  • Deborah G Siegel
  • E Rampersaud
  • Lorraine Mehltretter
  • Erik N Meyers
  • Michel Vekemans
  • Roger Ilagan
  • Susan H Slifer
  • Kristen L Deak
  • Rashmi Ahuja
  • Dietrich A Stephan
  • Allison Ashley-Koch
  • Yu Ping Yang
  • Ryan M Anderson
  • Shigeto Miura
  • Erica Sodergren
  • John A Kessler
  • Alexander G Bassuk
  • David S Enterline
  • I Washington Smoak
  • Eric R Detrait
  • M C Speer
  • Heather C Etchevers
  • Noah A Byrd
  • Uta Grieshammer
  • David McLone
  • Marion Walker
  • Timothy Brei
  • Joann Bodurtha
  • Elli Meeropol
  • Bermans Iskandar
  • Joanne Mackey
  • Kathleen Sawin
  • Simon G Gregory
  • Gordon Worley
  • W Jerry Oakes
  • Victoria Zismann
  • Philip Mack
  • Jessica J Connelly
  • Connie Buran
  • Nicole Lasarsky
  • Alison Trott
  • Nathen Ellis
  • Joy Ito
  • Nicole Reichenbach
  • Michael M Kessels
  • Laura Custer
  • Roser Pinyol
  • Britta Qualmann
  • John S Taylor
  • Donna Maglott
  • Christopher E Killian
  • Stephanie Bell
  • Andrew Leone
  • Lan Zhang
  • Gretchen Hofmann
  • Michelle M Roux
  • Clay Davis
  • Allison M Churcher
  • Pedro Martinez
  • Bruce P Brandhorst
  • Ronghui Xu
  • Nikki Adams
  • David R McClay
  • Elly Chow
  • Robert L Morris
  • David Epel
  • Pei Yun Lee
  • Paola Oliveri
  • Charles A Ettensohn
  • Richard O Hynes
  • Kai Jiao
  • Jia L Song
  • Ekaterina Voronina
  • Shannon Davis
  • Odile Mulner-Lorillon
  • Veronique Duboc
  • Rachel Thorn
  • Stefan C Materna
  • Anna T Neill

Detail Information

Publications22

  1. ncbi Expression of cyp26b1 during zebrafish early development
    Qingshun Zhao
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Gene Expr Patterns 5:363-9. 2005
    ..At later stages, 24 through 48 hpf, additional expression was found in the eyes, diencephalon, midbrain-hindbrain boundary, cerebellum, pectoral fin and the pharyngeal arch primordia...
  2. pmc High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35
    Demetra S Stamm
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Birth Defects Res A Clin Mol Teratol 76:499-505. 2006
    b>Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations...
  3. ncbi BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites
    Shigeto Miura
    Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, MD C4 10, C458, Research Triangle Park, NC 27709, USA
    Development 133:3767-75. 2006
    ..This suggests that BMP and FGF signaling function antagonistically during paraxial mesoderm development...
  4. pmc Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions
    Abee L Boyles
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Environ Health Perspect 114:1547-52. 2006
    Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect...
  5. pmc Protein tyrosine and serine-threonine phosphatases in the sea urchin, Strongylocentrotus purpuratus: identification and potential functions
    C A Byrum
    Developmental, Cell, and Molecular Biology Group, Box 91000, Duke University, Durham, NC 27708, USA
    Dev Biol 300:194-218. 2006
    ..Finally, to assess roles of annotated phosphatases in endomesoderm formation, a literature review of phosphatase functions in model organisms was superimposed on sea urchin developmental pathways to predict areas of functional activity...
  6. pmc The genome of the sea urchin Strongylocentrotus purpuratus
    Erica Sodergren
    Science 314:941-52. 2006
    ..This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes...
  7. ncbi The bone morphogenetic protein antagonist noggin regulates mammalian cardiac morphogenesis
    Murim Choi
    Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
    Circ Res 100:220-8. 2007
    ..These data indicate that antagonism of BMP signaling by Noggin plays a critical role in ensuring proper levels of cell proliferation and EMT during cardiac morphogenesis in the mouse...
  8. pmc Cordon-bleu is an actin nucleation factor and controls neuronal morphology
    Rashmi Ahuja
    Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
    Cell 131:337-50. 2007
    ..Correspondingly, Cobl depletion results in decreased dendritic arborization. Thus, Cobl is an actin nucleator controlling neuronal morphology and development...
  9. ncbi Refinement of 2q and 7p loci in a large multiplex NTD family
    Demetra S Stamm
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Birth Defects Res A Clin Mol Teratol 82:441-52. 2008
    ..Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of approximately 3.0 mapping to 2q33.1-q35 and 7p21.1-pter...
  10. pmc 3.6 kb genomic sequence from Takifugu capable of promoting axon growth-associated gene expression in developing and regenerating zebrafish neurons
    Ava J Udvadia
    University of Wisconsin Milwaukee, Department of Biological Sciences, Great Lakes WATER Institute UWM GLWI, 600 E Greenfield Avenue, Milwaukee, WI 53204, United States
    Gene Expr Patterns 8:382-8. 2008
    ..In addition, this sequence will also be useful for targeting gene expression to neurons during periods of growth and plasticity...
  11. ncbi Endogenous bone morphogenetic protein antagonists regulate mammalian neural crest generation and survival
    Ryan M Anderson
    Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Dev Dyn 235:2507-20. 2006
    ..Such defects reflect, at least in part, a function to limit apoptosis in neural crest cells. Noggin and Chordin, therefore, function together to regulate both the generation and survival of neural crest cells in mammalian development...
  12. ncbi Fgf8 is required for anterior heart field development
    Roger Ilagan
    Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
    Development 133:2435-45. 2006
    ..Analysis of downstream signaling components, such as phosphorylated-Erk and Pea3, identifies the AHF splanchnic mesoderm itself as a target for Fgf8 signaling...
  13. pmc Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10
    E Rampersaud
    Duke University Medical Center, Box 3445, Durham, NC 27710, USA
    J Med Genet 42:940-6. 2005
    b>Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world...
  14. pmc SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects
    Kristen L Deak
    Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710, USA
    Hum Genet 117:133-42. 2005
    b>Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified...
  15. ncbi Sonic hedgehog is required for cardiac outflow tract and neural crest cell development
    I Washington Smoak
    North Carolina State University, Raleigh, 27695, USA
    Dev Biol 283:357-72. 2005
    ..Our data suggest that SHH signaling does not act directly on NCCs as a survival factor, but rather acts to restrict the domains that NCCs can populate during early stages (e8.5-10.5) of cardiovascular and craniofacial development...
  16. pmc Human neural tube defects: developmental biology, epidemiology, and genetics
    Eric R Detrait
    Hopital Necker, Enfants Malades Unité INSERM U393, 149, rue de Sevres, 75743 Paris Cedex 15, France
    Neurotoxicol Teratol 27:515-24. 2005
    Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth ..
  17. ncbi Loss of Gbx2 results in neural crest cell patterning and pharyngeal arch artery defects in the mouse embryo
    Noah A Byrd
    Department of Pediatrics and Cell Biology, Neonatal Perinatal Research Institute, Genome Science Research Building II, Box 3471, Duke University Medical Center, Durham, NC 27710, USA
    Dev Biol 284:233-45. 2005
    ..Here, we demonstrate that Fgf8 and Gbx2 expression overlaps in regions of the developing pharyngeal arches and that they interact genetically during pharyngeal arch and cardiovascular development...
  18. ncbi FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons
    Uta Grieshammer
    Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, CA 94143 2711, USA
    Development 132:3847-57. 2005
    ..Thus, unlike other FGF family members, which regulate growth and branching morphogenesis of the collecting duct system, Fgf8 encodes a factor essential for gene regulation and cell survival at distinct steps in nephrogenesis...
  19. pmc Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing
    Abee L Boyles
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    Hum Hered 59:220-7. 2005
    ..Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies...
  20. pmc Potential for expanded power in linkage studies using the ALLEGRO and MERLIN software programs
    E Rampersaud
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    J Med Genet 42:e68. 2005
    ..We recently completed a genomic screen of neural tube defects using GENEHUNTER-PLUS and the more recent ALLEGRO...
  21. pmc The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms
    Rolf W Stottmann
    Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
    Dev Biol 295:647-63. 2006
    ..We show that this defect is due to elevated BMP4 signaling. Thus, Noggin is required for mammalian neurulation in two contexts, dependent on position along the rostrocaudal axis...
  22. pmc Blocking Dishevelled signaling in the noncanonical Wnt pathway in sea urchins disrupts endoderm formation and spiculogenesis, but not secondary mesoderm formation
    Christine A Byrum
    Department of Zoology, University of Hawaii at Manoa, Honolulu, Hawaii, USA
    Dev Dyn 238:1649-65. 2009
    ....