Stem cells hold the promise of a therapeutic approach for treating disease, the control of tissue regeneration, the delivery of therapeutic agents and potential for replacement of a diseased cell population. However, manipulation of stem cells can only be achieved by understanding how they are regulated. It is increasingly evident that this regulation is achieved by environmental cues emanating from their specialized environment (niche). While many signaling pathways influence stem cell activity, beta-catenin signaling profoundly impacts the stem cell fate, inducing divergent cellular responses when induced or ablated. Recently, we have shown that during intestinal development over-expressing Wnt/beta-catenin signaling in the stem cell niche impacts the stem cell's proliferative capacity. Based on this data we believe that the Wnt/beta-catenin signaling pathway plays an important role in establishing the developing intestinal stem cell niche and maintaining the mature niche in the adult. The goal of this study is to test the hypothesis that Wnt/beta-catenin signaling is organized in a temporal manner to establish the intestinal stem cell niche and in a spatial manner for maintenance of the proliferation-to-differentiation progression within the mature niche. To test this hypothesis we will use Wnt-reporter and DNTcf-4 expressing mice (ablated Wnt/beta-catenin signaling) to characterize the temporal and spatial expression pattern of Wnt/beta-catenin activity during the stem cell niche morphogenesis and adulthood. Additionally we will determine if spatial expression of Wnt/beta-catenin signaling is required to maintain the adult stem cell niche by dissecting and analyzing discrete cell strata within the niche. Disruption of the normal expression of Wnt/beta-catenin by induction of a beta-catenin signaling molecule or a DNTcf-4 molecule will determine the dependence of signaling upon crypt establishment and maintenance. Finally, DNA microarray analysis will identify global changes in gene expression between the cellular regions of the developing stem cell niche (wild-type and DNTcf-4 intestines) to directly determine the role of Wnt/beta-catenin signaling on stimulation of molecules and pathways. These proposed studies will directly examine the role of Wnt/beta-catenin signaling on maintenance of the stem cell niche and will shed insight into the regulatory control of intestinal stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068326-03
Application #
7227554
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Carrington, Jill L
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$314,412
Indirect Cost
Name
Oregon Health and Science University
Department
Dermatology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Smith, Nicholas R; Swain, John R; Davies, Paige S et al. (2018) Monoclonal Antibodies Reveal Dynamic Plasticity Between Lgr5- and Bmi1-Expressing Intestinal Cell Populations. Cell Mol Gastroenterol Hepatol 6:79-96
Yan, Kelley S; Janda, Claudia Y; Chang, Junlei et al. (2017) Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545:238-242
Smith, Nicholas R; Davies, Paige S; Levin, Trevor G et al. (2017) Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis. Cell Mol Gastroenterol Hepatol 3:389-409
Powell, Anne E; Anderson, Eric C; Davies, Paige S et al. (2011) Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res 71:1497-505
Anderson, Eric C; Wong, Melissa H (2010) Caught in the Akt: regulation of Wnt signaling in the intestine. Gastroenterology 139:718-22
Levin, Trevor G; Powell, Anne E; Davies, Paige S et al. (2010) Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 139:2072-2082.e5
Powell, Anne E; Shung, Chia-Yi; Saylor, Katherine W et al. (2010) Lessons from development: A role for asymmetric stem cell division in cancer. Stem Cell Res 4:3-9
Davies, Paige S; Powell, Anne E; Swain, John R et al. (2009) Inflammation and proliferation act together to mediate intestinal cell fusion. PLoS One 4:e6530
Davies, Paige S; Dismuke, Adria D; Powell, Anne E et al. (2008) Wnt-reporter expression pattern in the mouse intestine during homeostasis. BMC Gastroenterol 8:57
Sharma, Girish; Goalstone, Marc Lee (2007) Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells. Biochem Biophys Res Commun 354:1078-83

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