Expression of Homeobox Genes in the Gastrointestinal Tract

Differences in expression of homeobox transcription factors in proximal and distal human small intestine. Walters JRF, Howard A, Rumble HEE, Prathalingam SR, Shaw-Smith CJ, Legon S.Gastroenterology 1997;113:472-7. Summary: Walters et al. describe the presence of homeobox gene products along the horizontal axis of the human gastrointestinal tract. Their purpose was to investigate whether expression of homeobox transcription factors differs between duodenal and ileal segments of the intestine. Homeobox transcription factors play an important role in defining patterns of cellular differentiation. Reverse-transcription polymerase chain reactions (RT-PCR) were performed on intestinal RNA prepared from surgical specimens. PCR products were obtained using mixed sequence oligonucleotide primers based on conserved regions. These products were identified and their abundance was determined by Northern blot analysis. In the results of this study, the presence of 16 different homeobox genes was revealed in human small intestine and marked differences were seen in expression along the horizontal axis of the small intestine. The three most numerous products obtained had marked homology to the homeobox products described in rodent intestine and are known asCdx-1, Cdx-2, and Pdx-1. Furthermore, 13 human homeobox cluster genes (HOX genes) were identified. Pdx-1 was seen only in the duodenum. Cdx-1 was expressed more in distal small intestinal regions than was Cdx-2. Comment: Homeobox genes are known to play a key role in controlling morphogenesis and differentiation. The control of these aspects relies on exact timing of expression of these genes in a hierarchical order to define the fate of cell, tissue, and organ. A homeobox consist of a 180-base pair (bp) DNA sequence, which encodes a 60-amino acid protein product, the homeodomain protein. These proteins are DNA-binding and can therefore modulate the expression of target genes by binding to their respective promoters. The homeodomain proteins do not act in isolation but are members of a network of transcription factors. The homeobox gene was first discovered in the fruit fly Drosophila, and has now been identified as a general master developmental control gene in every multicellular organism (Pediatr Res 1997;42:421-9). To date, more than 170 homeobox genes have been identified. They have been categorized into two subfamilies: the clustered homeobox genes known asHOX genes and the divergent homeobox genes, which are scattered throughout the genome. The latter family forms groups based on sequence similarity. The clustered HOX genes are found on different chromosomes and they are seen as architects of the body plan. By mutating these genes, their role has been elucidated (Nature 1978;276:565-70). Mutant genes were able to transform one of the body segments into the appearance of another segment. Development of the gastrointestinal tract also relies on a hierarchy of signals in a coordinated program that rules proliferation and differentiation of cell lineages (Am J Physiol 1996;G50-6). Homeobox gene expression, which has a pivotal role in these processes, has first been described in the gastrointestinal tract in mice (Genes Dev 1988;2:1647-54 ; J Biol Chem 1991;266:3246-51). These genes showed a clear relationship with the gene Caudal, which was known to have an important role in defining a part of the body plan inDrosophila. The Caudal-related genes (Cdx) in the gastrointestinal tract are now known to modulate intestine-specific gene expression, including the expression of sucrase-isomaltase (Mol Cell Biol 1994;14:7340-51) and other genes. Pdx-1 is critical for development of the pancreas and for differentiation of the duodenum and is a regulator of the expression of the insulin gene in the beta-cells of the endocrine pancreas(EMBO J 1994;13:1145-56 ;Development 1996;122:983-95 ; Nat Genet 1997;15:106-10). Some HOX genes are known to be involved in organizing the smooth muscle layers that will finally form the internal anal sphincter (Development 1996;122:1175-85). The description of the presence of homeobox transcription factors in the human small intestine will ultimately lead to insight in the organogenesis, morphogenesis, and differentiation of the human intestinal tract(Gastroenterology 1997;113:472-7). To achieve this goal, descriptive studies in humans are performed in combination with experimental studies in which the function of these genes are tested. Loss of function of these gene products because of genetic faults could appear to be responsible for the pathogenesis of human congenital malformations of the gastrointestinal tract (Gastroenterology 1997;113:680-2). Beside the role of the homeobox genes in the pathophysiology of the construction of the gastrointestinal tract, homeobox transcription factors are supposedly factors that regulate and maintain the differentiated phenotype of the intestinal epithelium. This is currently undergoing investigation in regard to certain pathologic conditions, such as intestinal metaplasia and carcinoma, in which expression of homeobox genes is altered(Gastroenterology 1997; 113:478-86). Edmond Rings Merlijn van den Berg Pieter Stokkers Division of Pediatric Gastroenterology and Nutrition Academic Medical Center, G8-205; University of Amsterdam; Amsterdam, The Netherlands