Despite the prevalence of congenital defects of endodermally derived organs including the lungs, liver, pancreas and intestines, surprisingly little is known about the mechanisms that determine where the primordia for endodermal organs will form along the anterior-posterior (A-P) axis, which is the long-term goal of this research. Our published and preliminary studies show that endoderm patterning is highly conserved across vertebrate species and we hypothesize that that one growth factor, FGF4, plays a central role in establishing these gut tube domains in vivo. The expression pattern of FGF4 and our preliminary data suggest FGF4 patterns the gut tube by promoting posterior and repressing anterior endoderm cell fate. This proposal aims to determine the mechanisms by which this occurs. We show that FGF4 can directly regulate A-P endoderm cell fate and that FGF4 alters the normal path of migration of endoderm cells along the A-P axis in vivo, suggesting that both act to pattern the developing gut tube. Moreover, the FGF4-target genes that regulate endoderm patterning and gut tube development are largely unidentified. We have identified one endoderm specific, FGF4-responsive gene that encodes FGF binding protein 1 (FGFbp1). Our studies have determined that FGFbp1 is secreted, binds to FGF4, prevents it from becoming tethered to the extracellular matrix (ECM) and enhances its activity. These data support our hypothesis that FGFbpl acts as an endoderm-specific FGF4 agonist during endoderm and gut tube patterning. We will investigate the molecular mechanisms by which FGF4-signaling patterns the developing gut tube along the A-P axis with the following aims:
Aim 1. Determine the cell-biological mechanisms by which FGF4 establishes gut tube domains in vivo.
Aim 2. Investigate the role of evolutionarily conserved FGF4-target genes in endoderm patterning.
Aim 3. Investigate the function and mechanism of action of FGFbp1 during gut tube development. Lay Description: The proposed studies address an important question; how does one cell type, endoderm, give rise to cells of the lung, liver, pancreas, stomach, thyroid and intestine. Understanding normal development of these organs will allow us to diagnose congenital abnormalities. Additionally, this information should allow us to coax embryonic stem cells into becoming important transplantable derivatives of endoderm, such as insulin-producing beta cells to treat patients with Type 1 diabetes.
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| McCracken, Kyle W; Wells, James M (2012) Molecular pathways controlling pancreas induction. Semin Cell Dev Biol 23:656-62 |
| Du, Aiping; McCracken, Kyle W; Walp, Erik R et al. (2012) Arx is required for normal enteroendocrine cell development in mice and humans. Dev Biol 365:175-88 |
| McCracken, Kyle W; Howell, Jonathan C; Wells, James M et al. (2011) Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc 6:1920-8 |
| Kavanaugh, Gina M; Wise-Draper, Trisha M; Morreale, Richard J et al. (2011) The human DEK oncogene regulates DNA damage response signaling and repair. Nucleic Acids Res 39:7465-76 |
| Spence, Jason R; Mayhew, Christopher N; Rankin, Scott A et al. (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470:105-9 |
| Howell, Jonathan C; Wells, James M (2011) Generating intestinal tissue from stem cells: potential for research and therapy. Regen Med 6:743-55 |
| Mayhew, Christopher N; Wells, James M (2010) Converting human pluripotent stem cells into beta-cells: recent advances and future challenges. Curr Opin Organ Transplant 15:54-60 |
| Lin, Suh-Chin J; Wani, Maqsood A; Whitsett, Jeffrey A et al. (2010) Klf5 regulates lineage formation in the pre-implantation mouse embryo. Development 137:3953-63 |
| Zorn, Aaron M; Wells, James M (2009) Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol 25:221-51 |
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