Common disorders of the human gastrointestinal (GI) tract, including congenital malformations, inflammatory bowel, celiac and peptic ulcer disease, intestine-specific infections and cancer, result in considerable morbidity and mortality in the United States. Although the pathophysiology of many of these disorders is likely related in fundamental ways to mechanisms of normal gut development, the molecular regulation of cell differentiation and fetal development of the mammalian intestine is poorly understood. This is particularly true for the molecular basis of the interaction between gut epithelium and its underlying mesenchyme, a key regulator of intestinal development and homeostasis. This proposal seeks to exploit recent technological advances to initiate a systematic molecular analysis of mammalian intestinal development and organogenesis. We will begin by examining quantitative and qualitative changes in the gene transcription profile during the critical interval between 13 and 15 days in mouse gestation, when the gut endoderm undergoes an important cellular transition from a poorly differentiated, pseudostratified tissue into a primitive villous epithelium. Preliminary analysis of two separate Serial Analysis of Gene Expression (SAGE) libraries prepared from these developmental stages reveals statistically significant changes in the expression levels of a surprisingly small number of genes, including several putative regulators of intercellular communication, gene transcription, and intracellular signaling. Some of these changes are presumed to drive the acquisition of cellular fate and morphology and tissue form and function in the developing small bowel.
The Specific Aims of the project involve more detailed characterization of these SAGE libraries, a unique resource in the field, with a special view toward identifying some of the critical regulators of early intestinal epithelial differentiation and mesenchymal-epithelial interactions. We further propose to examine the sites of mRNA expression for genes predicted to function in intercellular interactions and hence begin to map key candidate signaling pathways in gut development as a prelude to developing practical strategies to examine gene function more directly. Finally, we will expand this analysis in space and in time, by investigating the dynamic alterations in gene expression at two additional stages in small bowel development, and at parallel stages in development of the stomach and colon. The resulting comprehensive analysis of mammalian gut development, quite possibly the first of its kind, will elucidate some essential aspects of normal developmental processes and should contribute to improved understanding and treatment of common disorders of the GI tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061139-04
Application #
6844756
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (O1))
Program Officer
May, Michael K
Project Start
2002-02-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2005
Total Cost
$299,250
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Verzi, Michael P; Stanfel, Monique N; Moses, Kelvin A et al. (2009) Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology 136:1701-10
Choi, Michael Y; Romer, Anthony I; Wang, Yang et al. (2008) Requirement of the tissue-restricted homeodomain transcription factor Nkx6.3 in differentiation of gastrin-producing G cells in the stomach antrum. Mol Cell Biol 28:3208-18
Verzi, Michael P; Khan, Abdul H; Ito, Susumu et al. (2008) Transcription factor foxq1 controls mucin gene expression and granule content in mouse stomach surface mucous cells. Gastroenterology 135:591-600
Van Dyck, Frederik; Braem, Caroline V; Chen, Zhao et al. (2007) Loss of the PlagL2 transcription factor affects lacteal uptake of chylomicrons. Cell Metab 6:406-13
Kim, Byeong-Moo; Miletich, Isabelle; Mao, Junhao et al. (2007) Independent functions and mechanisms for homeobox gene Barx1 in patterning mouse stomach and spleen. Development 134:3603-13
Kim, Byeong-Moo; Mao, Junhao; Taketo, Makoto M et al. (2007) Phases of canonical Wnt signaling during the development of mouse intestinal epithelium. Gastroenterology 133:529-38
Choi, Michael Y; Romer, Anthony I; Hu, Michael et al. (2006) A dynamic expression survey identifies transcription factors relevant in mouse digestive tract development. Development 133:4119-29
Hu, Michael; Shivdasani, Ramesh A (2005) Overlapping gene expression in fetal mouse intestine development and human colorectal cancer. Cancer Res 65:8715-22
Drori, Stavit; Girnun, Geoffrey D; Tou, Liqiang et al. (2005) Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev 19:362-75
Kim, Byeong-Moo; Buchner, Georg; Miletich, Isabelle et al. (2005) The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling. Dev Cell 8:611-22

Showing the most recent 10 out of 12 publications