Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk.

Reciprocal cross talk between the endodermally derived epithelium and the underlying mesenchyme is required for regional patterning and proper differentiation of the developing mammalian intestine. Though both epithelium and mesenchyme participate in patterning, the mesenchyme is thought to play a prominent role in the determination of the epithelial phenotype during development and in adult life. However, the molecular basis for this instructional dominance is unclear. In fact, surprisingly little is known about the cellular origins of many of the critical signaling molecules and the gene transcriptional events that they impact. Here, we profile genes that are expressed in the separate mesenchymal and epithelial compartments of the perinatal mouse intestine. The data indicate that the vast majority of soluble inhibitors and modulators of signaling pathways such as Hedgehog, Bmp, Wnt, Fgf, and Igf are expressed predominantly or exclusively by the mesenchyme, accounting for its ability to dominate instructional cross talk. We also catalog the most highly enriched transcription factors in both compartments. The results bolster previous evidence suggesting a major role for Hnf4gamma and Hnf4alpha in the regulation of epithelial genes. Finally, we find that while epithelially enriched genes tend to be highly tissue restricted in their expression, mesenchymally enriched genes tend to be broadly expressed in multiple tissues. Thus, the unique tissue-specific signature that characterizes the intestinal epithelium is instructed and supported by a mesenchyme that itself expresses genes that are largely nontissue specific.