Abstract
BackgroundIntestinal epithelial cells express the Sonic and Indian hedgehog ligands. Despite the strong interest in gut hedgehog signaling in GI diseases, no studies have specifically addressed the singular role of intestinal epithelial cell Sonic hedgehog signaling. The aim of this study was to investigate the specific role of Sonic hedgehog in adult ileal epithelial homeostasis.Methodology/Principal FindingsA Sonic hedgehog intestinal epithelial conditional knockout mouse model was generated. Assessment of ileal histological abnormalities, crypt epithelial cell proliferation, epithelial cell fate, junctional proteins, signaling pathways, as well as ultrastructural analysis of intracellular organelles were performed in control and mutant mice. Mice lacking intestinal epithelial Sonic Hedgehog displayed decreased ileal crypt/villus length, decreased crypt proliferation as well as a decrease in the number of ileal mucin-secreting goblet cells and antimicrobial peptide-secreting Paneth cells during adult life. These secretory cells also exhibited disruption of their secretory products in mutant mice. Ultrastructural microscopy analysis revealed a dilated ER lumen in secretory cells. This phenotype was also associated with a decrease in autophagy.Conclusions/SignificanceAltogether, these findings indicate that the loss of Sonic hedgehog can lead to ileal secretory cell modifications indicative of endoplasmic reticulum stress, accompanied by a significant reduction in autophagy.
Highlights
Morphogens are soluble molecules which form patterning gradients in tissues [1] and play key roles in adult tissue and cell homeostasis
To investigate the profile of Sonic hedgehog (Shh) ligand expression in epithelial cells, epithelial populations from the mouse intestinal mucosa were progressively isolated along the villus-to-crypt axis using a modified Weiser procedure [29]
Despite increasing interest in gut Hedgehog ligands (Hh) signaling, very little is known regarding the specific roles played by Shh in intestinal epithelial cell function and homeostasis
Summary
Morphogens are soluble molecules which form patterning gradients in tissues [1] and play key roles in adult tissue and cell homeostasis. Shh mutants exhibit anterior expansion of the glandular stomach, increased gland fission, duodenal obstruction and abnormal innervation of the gut in addition to expressing certain markers reminiscent of early intestinal transformation of the stomach [1,3] whereas Ihh mutants exhibit reduced epithelial stem cell proliferation and differentiation [4]. Based on these data, it was assumed that Hh ligands produced by intestinal epithelial cells could act on the mesenchyme through paracrine signaling, thereby inducing mesenchymal signals including Secreted-frizzledrelated proteins (SFRP1 and 2) and Bone morphogenetic proteins (Bmps) affecting intestinal epithelial cell proliferation as well as differentiation by antagonizing Wnt signaling [2,5,6,7,8,9]. The aim of this study was to investigate the specific role of Sonic hedgehog in adult ileal epithelial homeostasis
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