Basic–alimentary tractPPARβ/δ Regulates Paneth Cell Differentiation Via Controlling the Hedgehog Signaling Pathway
Section snippets
L-165041
The PPARβ–selective agonist L-165041 (4-[3-[2-propyl-3-hydroxy-4-acetyl] phenoxy] propyloxyphenoxy acetic acid)29 was synthesized in our laboratory but now is available commercially (cat# 422175; Calbiochem; Dormstadt, Germany).
Animals
All animals had free access to a standard laboratory chow diet in a temperature- and light-controlled environment. PPARβ-null mice and their control wild-type were bred on a mixed genetic background (SV129 and C57BL/6) and were killed at 10 weeks of age. After death by CO
Expression Pattern of PPARβ in the Adult Mouse Small Intestine
PPARβ is expressed in all parts of the small intestine in the mouse, with the highest expression in the duodenal mucosa (Figure 1A). It is present mainly in the epithelial cells, with a decreasing gradient of expression from the bottom to the top of the villi (Figure 1B). The highest PPARβ expression is at the bottom of the crypts, with a marked decrease from cell position 9 upward (Figure 1C).
PPARβ-Null Mutation Impairs Paneth Cell Differentiation
In addition to Paneth cells, stem cells (for which the lack of a reliable marker limits determination
Discussion
Our work reveals the importance of the Ihh signaling pathway for Paneth cell maturation and its control by PPARβ. We propose that the intensity of the Ihh signal received by the precursor cells reflects the number of mature Paneth cells in the crypt. High Ihh levels repress maturation of Ptch-1–positive cells, confining them in their precursor state, whereas a weaker hedgehog signal attenuates the positive feedback loop on Ptch-1 expression, driving the terminal differentiation of precursor
References (64)
- et al.
Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice
J Biol Chem
(1997) - et al.
Identification of GM-CSF in Paneth cells using single-cell RT-PCR
Biochem Biophys Res Commun
(2003) - et al.
Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors
Cell
(1992) - et al.
Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway
Mol Cell
(2002) - et al.
Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity
Cell
(2003) - et al.
Novel peroxisome proliferator-activated receptor (PPAR)gamma and PPARdelta ligands produce distinct biological effects
J Biol Chem
(1999) - et al.
Activation of PPARdelta alters lipid metabolism in db/db mice
FEBS Lett
(2000) - et al.
Sonic hedgehog regulates gastric gland morphogenesis in man and mouse
Gastroenterology
(2001) - et al.
Effects of oligosaccharide on the faecal flora and non-specific immune system in elderly people
Nutr Res
(2002) - et al.
Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB
Cell
(2002)
Disruption of hedgehog signaling reveals a novel role in intestinal morphogenesis and intestinal-specific lipid metabolism in mice
Gastroenterology
Characterization of human bone morphogenetic protein (BMP)-4 and -7 gene promotersactivation of BMP promoters by Gli, a sonic hedgehog mediator
Bone
Differentiation-associated antimicrobial functions in human colon adenocarcinoma cell lines
Exp Cell Res
Identification of a putative intestinal stem cell and early lineage marker; musashi-1
Differentiation
Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo
Dev Biol
The hedgehog signalling pathway in the gastrointestinal tractimplications for development, homeostasis, and disease
Gastroenterology
PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs
Cell
Crohn’s disease and the NOD2 genea role for Paneth cells
Gastroenterology
Degranulation of Paneth cells via toll-like receptor 9
Am J Pathol
Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis
Cell
Clinical and pathological differentiation of Crohn’s disease and proctocolitis
Gastroenterology
Linking colorectal cancer to Wnt signaling
Cell
Paneth cell differentiation in the developing intestine of normal and transgenic mice
Proc Natl Acad Sci U S A
Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells
Proc Natl Acad Sci U S A
The multifaceted Paneth cell
Cell Mol Life Sci
Detection of CD1 mRNA in Paneth cells of the mouse intestine by in situ hybridization
J Histochem Cytochem
Ultrastructural localization of tumour necrosis factor-alpha
Histochem J
Prostaglandin E2 localization in the rat ileum
Histochem J
Paneth cells express high levels of CD95 ligand transcriptsa unique property among gastrointestinal epithelia
Am J Pathol
Requirement of Math1 for secretory cell lineage commitment in the mouse intestine
Science
Canonical Wnt signals are essential for homeostasis of the intestinal epithelium
Genes Dev
Wnt signalling induces maturation of Paneth cells in intestinal crypts
Nat Cell Biol
Cited by (100)
Pregnane X receptor (PXR) represses osteoblast differentiation through repression of the Hedgehog signaling pathway
2022, Experimental Cell ResearchThe Intestinal Stem Cell Niche: Homeostasis and Adaptations
2018, Trends in Cell BiologyNotch Pathway Regulation of Intestinal Cell Fate
2018, Physiology of the Gastrointestinal Tract, Sixth EditionHedgehog Signaling in Gastrointestinal Morphogenesis and Morphostasis
2018, Physiology of the Gastrointestinal Tract, Sixth EditionRequirement of Gα<inf>q</inf>/Gα<inf>11</inf> Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis
2016, Cellular and Molecular Gastroenterology and HepatologyTranscriptional control of physiological and pathological processes by the nuclear receptor PPARβ/δ
2016, Progress in Lipid ResearchCitation Excerpt :PPARβ/δ is highly expressed in the small and large intestines in rodents and humans, and in situ hybridization studies have shown that this nuclear receptor is expressed throughout the intestinal epithelium, with higher expression at the bottom of the crypts. Function of PPARβ/δ has been proposed in Paneth cells, enteroendocrine cells and enterocytes [221]. Two models are classically used for in vivo studies of CRC development.
Present addresses: Department of Cardiology, Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland (P.G.); Department of Cell Physiology and Metabolism, Geneva Medical School, CH-1211 Genève 04, Switzerland (N.B.).
Supported by the Etat de Vaud, Nestlé Research Center, and grants from the Swiss National Science Foundation (B.D. and W.W.).