Expression of a Novel Cadherin in the Mouse and Human Intestine

Abstract

Members of the cadherin superfamily mediate critical interactions in tissue differentiation and organogenesis, including differentiation and maintenance of the intestine. In this study, we report the identification and expression of a novel cadherin in the intestinal epithelium. We identified this cDNA by subtraction hybridization and obtained subsequent clones by screening a human cDNA library. Tissue distribution of the mRNA encoding the cadherin was assessed by RNA blot, reverse transcriptase PCR, and in situ hybridization. Protein expression was analyzed by protein blot and immunohistochemistry. The cDNA encodes an integral membrane protein with four consecutive cadherin binding domains followed by a series of mucin domains, a unique feature of this cadherin. Differences in the mucin domains account for four splice-forms. Multiple potential SH3-binding domains and a single potential PDZ-binding domain follow the transmembrane domain. Analysis revealed expression in the liver, kidney, and intestine. Three splice variants were found in the embryonic intestine as early as embryonic d 13 and in the adult intestine. The mRNA localizes to the mature enterocytes throughout the mouse small intestine and the protein, including several species from 90 to 100 kD, resides on the enterocyte basolateral membrane. We have identified intestinal expression of a novel cell cadherin with features suggesting the potential to transduce signals from neighboring cells to the cytoplasm. The intestinal epithelium undergoes a rapid and continuous process of cellular renewal involving cell turnover and regeneration (1, 2). Cell turnover entails a sequence of cell proliferation, differentiation, migration, and programmed cell death. Pluripotential epithelial stem cells reside near the base of each crypt of Lieberkuhn and provide a continuous supply of mature epithelial cells. Daughter cells that arise from these stem cells proliferate rapidly and differentiate during a bipolar migration into one of four principle epithelial cell lineages. As a result, enterocytes, goblet cells, and enteroendocrine cells populate the villus epithelium whereas Paneth cells reside at the base of the crypts along with stem cells (3, 4). Cell lineages undergo differentiation as they migrate up the epithelial villus. After 3-5 d, cells on the villous tip are shed through a process involving apoptosis (5-7). Consequently, development and maintenance of normal intestinal epithelial morphology requires tight regulatory control of cell proliferation, migration, and differentiation along the crypt-villus axis.The coordination of these processes in building the normal architecture of the intestinal epithelium depends on selective interactions of the cells with other cells and with the extracellular matrix (8, 9). Multiple molecules have been identified that mediate intercellular and cell-to-matrix adhesive functions (10 -12). Most belong to one of a few supergene families, the selectin, the immunoglobulin, the integrin, or the cadherin families. Members of the int...

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