b-catenin's role in establishing the gut stem cell niche

Summary

Principal Investigator: Melissa Wong
Abstract: 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.
Funding Period: 2005-05-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc Wnt-reporter expression pattern in the mouse intestine during homeostasis
    Paige S Davies
    Department of Dermatology, Oregon Cancer Center, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA
    BMC Gastroenterol 8:57. 2008
  2. pmc Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract
    Trevor G Levin
    Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Stem Cell Center, Portland, Oregon, USA
    Gastroenterology 139:2072-2082.e5. 2010
  3. pmc Lessons from development: A role for asymmetric stem cell division in cancer
    Anne E Powell
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    Stem Cell Res 4:3-9. 2010
  4. pmc Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming
    Anne E Powell
    Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Stem Cell Center, Portland, Oregon, USA
    Cancer Res 71:1497-505. 2011
  5. pmc Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells
    Girish Sharma
    University of Colorado at Denver and Health Sciences Center, Aurora, CO 80220, USA
    Biochem Biophys Res Commun 354:1078-83. 2007
  6. pmc Inflammation and proliferation act together to mediate intestinal cell fusion
    Paige S Davies
    Department of Dermatology, Knight Cancer Institute, Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 4:e6530. 2009
  7. ncbi Dominant-negative alpha-subunit of farnesyl- and geranyltransferase inhibits glucose-stimulated, but not KCl-stimulated, insulin secretion in INS 832/13 cells
    Rajakrishnan Veluthakal
    Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI 48201, USA
    Diabetes 56:204-10. 2007
  8. pmc Myeloid lineage progenitors give rise to vascular endothelium
    Alexis S Bailey
    Oregon Stem Cell Center, Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, 97239, USA
    Proc Natl Acad Sci U S A 103:13156-61. 2006
  9. pmc Bone marrow-derived cells fuse with normal and transformed intestinal stem cells
    Adnan Z Rizvi
    Department of Surgery, Division of Hematology and Medical Oncology, and Oregon Cancer Institute, Oregon Stem Cell Center, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
    Proc Natl Acad Sci U S A 103:6321-5. 2006
  10. ncbi Dominant negative FTase (DNFTalpha) inhibits ERK5, MEF2C and CREB activation in adipogenesis
    Girish Sharma
    The Department of Medicine, University of Colorado, Denver Health Sciences Center, Denver, 80220, USA
    Mol Cell Endocrinol 245:93-104. 2005

Detail Information

Publications11

  1. pmc Wnt-reporter expression pattern in the mouse intestine during homeostasis
    Paige S Davies
    Department of Dermatology, Oregon Cancer Center, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA
    BMC Gastroenterol 8:57. 2008
    ..This important determination has implications on intestinal function, especially during epithelial expansion and regeneration, and warrants an extensive characterization of Wnt-activated cells...
  2. pmc Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract
    Trevor G Levin
    Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Stem Cell Center, Portland, Oregon, USA
    Gastroenterology 139:2072-2082.e5. 2010
    ..Although the presence of CD166 at the tumor cell surface has been correlated with shortened survival, little is known about its function and expression in normal intestinal epithelia...
  3. pmc Lessons from development: A role for asymmetric stem cell division in cancer
    Anne E Powell
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    Stem Cell Res 4:3-9. 2010
    ..This highlights an important new focus for understanding the mechanism underlying expansion of cancer stem cells in driving tumorigenesis...
  4. pmc Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming
    Anne E Powell
    Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Stem Cell Center, Portland, Oregon, USA
    Cancer Res 71:1497-505. 2011
    ..As such, cell fusion may represent a promising novel mechanism underlying the metastatic conversion of cancer cells...
  5. pmc Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells
    Girish Sharma
    University of Colorado at Denver and Health Sciences Center, Aurora, CO 80220, USA
    Biochem Biophys Res Commun 354:1078-83. 2007
    ..Taken together, these data indicate that insulin and A-II regulate the activity of ERK5, but different from that seen for ERK1/2...
  6. pmc Inflammation and proliferation act together to mediate intestinal cell fusion
    Paige S Davies
    Department of Dermatology, Knight Cancer Institute, Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 4:e6530. 2009
    ....
  7. ncbi Dominant-negative alpha-subunit of farnesyl- and geranyltransferase inhibits glucose-stimulated, but not KCl-stimulated, insulin secretion in INS 832/13 cells
    Rajakrishnan Veluthakal
    Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI 48201, USA
    Diabetes 56:204-10. 2007
    ..Together, our findings provide the first evidence for the regulation of GSIS by PPTase in INS 832/13 cells. Furthermore, they support our original hypothesis that prenylation of specific G-proteins may be necessary for GSIS...
  8. pmc Myeloid lineage progenitors give rise to vascular endothelium
    Alexis S Bailey
    Oregon Stem Cell Center, Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, 97239, USA
    Proc Natl Acad Sci U S A 103:13156-61. 2006
    ..Our findings indicate that endothelial cells are an intrinsic component of myeloid lineage differentiation and underscore the close functional relationship between the hematopoietic and vascular systems...
  9. pmc Bone marrow-derived cells fuse with normal and transformed intestinal stem cells
    Adnan Z Rizvi
    Department of Surgery, Division of Hematology and Medical Oncology, and Oregon Cancer Institute, Oregon Stem Cell Center, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
    Proc Natl Acad Sci U S A 103:6321-5. 2006
    ..Fusion of BMDCs with neoplastic epithelium did not result in tumor initiation. Our findings suggest an unexpected role for BMDCs in both regeneration and tumorigenesis of the intestine...
  10. ncbi Dominant negative FTase (DNFTalpha) inhibits ERK5, MEF2C and CREB activation in adipogenesis
    Girish Sharma
    The Department of Medicine, University of Colorado, Denver Health Sciences Center, Denver, 80220, USA
    Mol Cell Endocrinol 245:93-104. 2005
    ..Taken together, these data suggest that prenylation plays a critical role in insulin-stimulated adipogenesis, and that the ERK5 plays an important, but less crucial role in adipogenesis as compared to ERK1/2...