Epithelial and Mesenchymal Cell Biology Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine

Members of the Ets transcription factor family are widely expressed in both the developing and mature mammalian intestine, but their biological functions remain primarily uncharacterized. We used a dominant repressor transgene approach to probe the function of epithelial Ets factors in the homeostasis of the crypt-villus unit, the functional unit of the small intestine. We show that targeted expression in small intestinal epithelium of a fusion protein composed of the Engrailed repressor domain and the Erm DNAbinding domain (En/Erm) results in marked disruption of normal crypt-villus homeostasis, including a cell-autonomous disturbance of epithelial maturation, increased epithelial transit , severe villus dysmorphogenesis, and crypt dysmorphogenesis. The epithelial maturation disturbance is independent of the regulation of TGF RII levels, in contrast to Etsmediated epithelial differentiation during development; rather, regulation of Cdx2 expression may play a role. The villus dysmorphogenesis is independent of alterations in the crypt-villus boundary and inappropriate -catenin activation, and thus appears to represent a new mechanism controlling villus architectural organization. An Analysis of animals mosaic for En/Erm expression suggests that crypt nonautonomous mechanisms underlie the crypt dysmorphogenesis phenotype. Our studies thus uncover novel Ets-regulated pathways of intestinal homeostasis in vivo. Interestingly, the overall En/Erm phenotype of disturbed crypt-villus homeostasis is consistent with recently identified Ets function(s) in the restriction of intestinal epithelial tumorigenesis. (Am J Pathol 2009, 174:1280–1290; DOI: 10.2353/ajpath.2009.080409) Ets factors comprise a large family of transcription factors found in metazoans. Numbering as many as 27 in humans, Ets factors are related to each other by a conserved DNA-binding domain (DBD), the Ets domain. The Ets domain is a winged helix-turn-helix structural motif, which binds to a core GGA(A/T) DNA sequence. On binding to DNA, Ets factors regulate gene promoter activity directly via intrinsic activation or, less commonly, repression domains, or indirectly through interactions with other transcription factors. Frequently acting as nuclear effectors of growth factor receptor-mediated signaling pathways, Ets factors control the expression of genes involved in diverse cellular processes, including cell proliferation, apoptosis, differentiation, and cell-cell/ cell-matrix interactions. Ets factors are widely expressed in a variety of developing and adult mammalian tissues. Genetic inactivation of individual Ets factors in the mouse has revealed unique, essential Ets functions in diverse biological processes, including hematopoiesis, immune function, lymph/angiogenesis, neurogenesis/neuromuscular function, spermatogenesis, early embryonic patterning, and development of extraembryonic tissues. Interestingly, such studies have been remarkable for the absence of phenotypes in a number of tissues with Ets expression, especially those comprising solid organs. The relative paucity of Ets phenotypes in such tissues appears to be attributable to the multiplicity of expression of different Ets factors in the same cell, combined with the