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 Gut Development |
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  Background- The vertebrate gastrointestinal tract develops as a result of crucial inductive interactions between cells derived from the embryonic endodermal and mesodermal germ layers. The endoderm gives rise to the epithelial lining of the whole aerodigestive tract, whereas the adjacent splanchnic mesoderm produces the surrounding mesenchyme and smooth muscle. To understand the cellular and molecular basis of gut development , it is important to study (1) early aspects of endoderm specification, (2) differentiation of primitive endoderm into gut-specific epithelium, (3) patterning of the endoderm into foregut, midgut, and hindgut segments, and (4) the nature of the intercellular communication between endodermal and mesodermal cell compartments. Barx1 in stomach development
The gut tube is patterned early in development to distinguish the stomach from the caudally located intestine segments. The homeodomain transcription factor Barx1 is selectively expressed in rostral stomach mesenchyme and determines the identity of the overlying undifferenitated endoderm. Barx1 specifies stomach epithelium by regulating expression of secreted wnt antagonists, and in its absence the stomach develops with intestinal character. The lab is actively investigating functions of Barx1 in stomach development. Cancer genes in gut development
Signaling by Wnt, Hedgehog and Notch ligands is essential for differentiation of many vertebrate cell types. Working in collaboration with scientists at Genentech Inc, we showed that down-regulation of hedgehog signaling is required for proper cytodifferentiation of the Xenopus bowel epithelium. A positive role for hedgehog signaling in early GI development has been addressed by several laboratories. In emphasizing the need for hedgehog signals to be attenuated later in development, our results illustrate the dynamic aspect of cell-cell signaling in organogenesis. More recently, we have taken a systematic approach to estimate and probe the extent of overlap in gene expression during organogenesis and in tumors of the same fetal origin. These studies focus on human colorectal cancer and mouse intestine development. Transcriptional control of GI differentiation To obtain an unbiased and comprehensive perspective on the changes in gene expression that accompany GI development, we have used conventional mRNA expression profiling and a unique approach to measure transcription factor mRNA levels. We first assessed all genes using Serial Analysis of Gene Expression (SAGE) and the results are accessible to the public (http://genome.dfci.harvard.edu/gutsage). Our subsequent emphasis has been on studying signaling molecules and transcription factors whose mRNA levels change significantly during mouse gut development, and hence on identifying potential determinants of cellular and tissue transitions. More recently, we took a systematic approach to catalog expression of all transcription factor genes during mouse GI development. This study uncovered stage- and region-specific expression of dozens of transcription factor mRNAs. These data will also soon be made available to the public and we hope they will stimulate further research into the transcriptional determinants of discrete cells and GI regions. Endoderm specification Early endoderm differentiation in flies and worms is critically dependent on transcription factors of the GATA family. We have shown that the principal endoderm determinant in C. elegans, the GATA protein END-1, is also a potent inducer of endoderm in Xenopus embryos and that dominant-negative End-1 constructs inhibit endogenous Xenopus endoderm development. Independently, other laboratories have documented the importance of GATA proteins in early vertebrate endoderm development TRPS1 in development An interesting difference between known vertebrate GATA proteins (GATA-1 to GATA-6) and invertebrate GATA factors that induce endoderm development is the number of GATA-type zinc fingers: 2 in the vertebrate class versus 1 in invertebrate proteins. We hypothesized that vertebrate genomes might also encode single-zinc finger GATA proteins and isolated TRPS1, probably the only vertebrate GATA protein of this class. Other groups have implicated TRPS1 in inherited human tricho-rhino-phalangeal syndromes, types I and II (Momeni et al., Ludecke et al.), and mice lacking the GATA-type zinc finger of TRPS1 show skeletal developmental anomalies similar to the human disease (Malik et al.). |
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