PPARbeta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway.
OBJECTIVE
All 4 differentiated epithelial cell types found in the intestinal epithelium derive from the intestinal epithelial stem cells present in the crypt unit, in a process whose molecular clues are intensely scrutinized. Peroxisome proliferator-activated receptor beta (PPARbeta) is a nuclear hormone receptor activated by fatty acids and is highly expressed in the digestive tract. However, its function in intestinal epithelium homeostasis is understood poorly.


METHODS
To assess the role of PPARbeta in the small intestinal epithelium, we combined various cellular and molecular approaches in wild-type and PPARbeta-mutant mice.


RESULTS
We show that the expression of PPARbeta is particularly remarkable at the bottom of the crypt of the small intestine where Paneth cells reside. These cells, which have an important role in the innate immunity, are strikingly affected in PPARbeta-null mice. We then show that Indian hedgehog (Ihh) is a signal sent by mature Paneth cells to their precursors, negatively regulating their differentiation. Importantly, PPARbeta acts on Paneth cell homeostasis by down-regulating the expression of Ihh, an effect that can be mimicked by cyclopamine, a known inhibitor of the hedgehog signaling pathway.


CONCLUSIONS
We unraveled the Ihh-dependent regulatory loop that controls mature Paneth cell homeostasis and its modulation by PPARbeta. PPARbeta currently is being assessed as a drug target for metabolic diseases; these results reveal some important clues with respect to the signals controlling epithelial cell fate in the small intestine.
Varnat
Frédéric
F
Center for Integrative Genomics, National Research Centre Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland.
Heggeler
Béatrice Bordier-Ten
BB
Grisel
Philippe
P
Boucard
Nathalie
N
Corthésy-Theulaz
Irène
I
Wahli
Walter
W
Desvergne
Béatrice
B
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004627:Embryonic Induction; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009154:Mutation; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019879:Paneth Cells / Q000378:metabolism* / Q000648:ultrastructure*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014704:Veratrum Alkaloids / Q000494:pharmacology
D053823:Hedgehog Proteins; D048068:PPAR-beta; D012333:RNA, Messenger; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C000541:cyclopamine