The long-term goal of this proposal is to elucidate the molecular program controlling early liver development. The liver provides many essential functions and numerous liver pathologies are so life threatening that transplantation is the only option. Despite its physiological importance the molecular basis of liver development is poorly understood. A better understanding of liver development will provide insight into congenital liver disease and facilitate efforts to produce therapeutically useful hepatic tissue from stem cells. The liver is derived from the embryonic endoderm through a series of inductive interactions that are conserved in vertebrates. While we increasingly understand the genes regulating liver formation after the hepatic specification, how the endoderm is patterned to establish the foregut domain that responds to hepatic induction is poorly understood. We propose to address this using the experimental advantages of the Xenopus embryo, which are ideal for studying very early embryogenesis. We will test the hypothesis that secreted Wnt-antagonists in the anterior endoderm are required to establish the foregut domain and promote liver development, by inhibiting Wnt signals from the axial/lateral mesoderm.
Aim 1 : Characterize the Wnt-antagonists and Wnt ligands that regulate endoderm patterning in vivo.
Aim 2 : Determine the mechanism by which Wnt-mediated patterning establishes the foregut domain, by examining the transcriptional regulation of the Hex promoter.
Aim 3 : Characterize the molecular events downstream of Wnt-repression mediating liver development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070858-03
Application #
7591694
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Serrano, Jose
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$301,350
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zorn, Aaron M (2017) Development of the digestive system. Semin Cell Dev Biol 66:1-2
Stevens, Mariana L; Chaturvedi, Praneet; Rankin, Scott A et al. (2017) Genomic integration of Wnt/?-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs. Development 144:1283-1295
MĂșnera, Jorge O; Sundaram, Nambirajan; Rankin, Scott A et al. (2017) Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. Cell Stem Cell 21:51-64.e6
Aslan, Yetki; Tadjuidje, Emmanuel; Zorn, Aaron M et al. (2017) High-efficiency non-mosaic CRISPR-mediated knock-in and indel mutation in F0 Xenopus. Development 144:2852-2858
Nolan, Kristof; Kattamuri, Chandramohan; Rankin, Scott A et al. (2016) Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism. Cell Rep 16:2077-2086
Agricola, Zachary N; Jagpal, Amrita K; Allbee, Andrew W et al. (2016) Identification of genes expressed in the migrating primitive myeloid lineage of Xenopus laevis. Dev Dyn 245:47-55
Rankin, Scott A; Han, Lu; McCracken, Kyle W et al. (2016) A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification. Cell Rep 16:66-78
Zhang, Zheng; Rankin, Scott A; Zorn, Aaron M (2016) Syndecan4 coordinates Wnt/JNK and BMP signaling to regulate foregut progenitor development. Dev Biol 416:187-199
LaBonne, Carole; Zorn, Aaron M (2015) Modeling human development and disease in Xenopus. Preface. Dev Biol 408:179
Nolan, Kristof; Kattamuri, Chandramohan; Luedeke, David M et al. (2015) Structure of neuroblastoma suppressor of tumorigenicity 1 (NBL1): insights for the functional variability across bone morphogenetic protein (BMP) antagonists. J Biol Chem 290:4759-71

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