Cell and Developmental Biology University of Michigan

Research

Molecular mechanisms of intestinal organogenesis; stem cells of the stomach; hedgehog signaling in intestinal development and disease

Cell: cell communication during the development of the small intestine

The goal of this project is to learn more about the constant signaling crosstalk between intestinal epithelium and mesenchyme that acts to pattern the intestine. In earlier studies, we demonstrated that Indian and Sonic Hedgehog, secreted from the intestinal epithelium, are required for patterning both the mesenchyme and the epithelium itself. Mesenchymal patterning is due to a direct paracrine hedghog signal. Events downstream of hedgehog signals include the localization of Wnt-secreting myofibroblasts beneath the pre-crypt regions of the intestine and the generation of smooth muscle structures in the cores of the villi. Epithelial patterning downstream of hedgehog signals is indirect and is controlled by secondary signals secreted from the mesenchyme, including Wnt, Bmp, and others. The location of the epithelial proliferative compartment is controlled in this way. In addition, we recently found that the generation of intestinal villi is a hedgehog-dependent morphogenic event. Using microarray, we are identifying the specific genes in mesenchymal cells that are targets for the hedgehog signal, concentrating on those genes that encode products that could generate secondary signals which impact epithelial function.

Patterning of the epithelial pyloric border

We are trying to understand how an intestinal cell "decides" to be intestine rather than stomach. We have identified the precise time during mouse development at which a distinct border forms in the previously un-patterned epithelium, separating stomach from intestine. The process that regulates this identity decision may be altered in cases of intestinal metaplasia, lesions of the stomach in which the stomach epithelium takes on the appearance of intestine. Intestinal metaplasia is associated with the development of gastric cancer, making this identity program a critical target for further research. stomach stem cells

Characterization of a novel stomach stem cell population

We have found the first marker by which a rare type of stomach stem cell can be prospectively recognized and isolated from the adult stomach. We have shown that these cells have multilineage potential and that they can give rise to all of the cells in a gastric gland. Interestingly, this cell population is greatly increased during inflammation or by the pro-inflammatory cytokine, interferon gamma. Because the gastric stem cell compartment is the likely target of mutations that promote tumors, and because tumorigenesis in the stomach is highly associated with chronic inflammation, we expect that the further characterization of this cell population will have major implications for gastric cancer.

Lab Members

• Ken Taniguchi
  Postdoctoral Fellow
• Michelle Muza-Moons
  Research Fellow
• Ajay Prakash
  Graduate Student
• Ram Vinod Roy
  Research Fellow
• Katherine Walton
  Research Fellow
• Kara Hamilton
  Lab Manager
• Jierong Lang
  Research Lab Technician
• Xiaotan Qiao
  Research Lab Specialist
• Neil Richards
  Research Lab Specialist
• Katherine Gurdziel
  Graduate Student
• Gibrael Barlaskar
  Undergradate Student
• Lauren Curley
  Undergradate Student
• Juhi Kushwaha
  Undergradate Student
• Caitlynn Lefler
  Undergradate Student
• Shawn Lopez
  Undergradate Student
• Sherrita McClain
  Undergradate Student
• Brianna Sabol
  Undergradate Student

Publications

Representative Publications

1. Braunstein, E.M., Qiao, T., Madison, B., Pinson, K. Dunbar, L., and Gumucio, D.L. Villin: a marker for development of the epithelial pyloric border. Dev. Dyn. 224:90-102, 2002.
2. Madison, B., Qiao, T., Braunstein, E., Dunbar, L., and Gumucio, D.L Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277:33275-33283, 2002.
3. Rieder, G., Tessier, A.J., Qiao, X.T., Madison, B., Gumucio, D. and Merchant, J.L.: Helicobacter-induced intestinal metaplasia in the stomach correlates with Elk-1 and serum response factor induction of villin. J. Biol. Chem. 280:4906-12, 2005.
4. Madison, B., Braunstein, K., Qiao, X., Kuizon, E., and Gumucio, D.: Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132:279-89, 2005.
5. Jones, R.G., Li, X., Gray, P.D., Kuang, J., Clayton, F., Samowitz, W.S., Madison, B.B., Gumucio, D.L. and Kuwada, S. K.: Conditional deletion of beta1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia and early postnatal lethality. J. Cell Biol. 175:505-14, 2006.
6. Li X, Madison BB, Zacharias W, Kolterud A, States D, Gumucio DL: Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk. Physiol Genomics. 29:290-301, 2007.
7. Kolterud A, Grosse AS, Zacharias WJ, Walton KD, Kretovich KE, Madison BB, Waghray M, Ferris JE, Hu C, Merchant JL, Dlugosz AA, Kottmann AH, Gumucio DL. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology. 137:618-28, 2009.
8. Li X, Udager AM, Hu C, Qiao XT, Richards N, Gumucio DL. Dynamic patterning at the pylorus: formation of an epithelial intestine-stomach boundary in late fetal life. Dev Dyn. 238:3205-17, 2009.
9. Zacharias WJ, Li X, Madison BB, Kretovich K, Kao JY, Merchant JL, Gumucio DL. Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria. Gastroenterology. 138:2368-77, 2010.