Sonic hedgehog regulates gastric gland morphogenesis in man and mouse.
OBJECTIVE
Gastric epithelial renewal is an asymmetric process. A stem cell located halfway up the tubular unit gives rise to both a basal gland region and a luminal pit compartment, but the mechanisms responsible for the maintenance of this asymmetry are obscure. We investigated whether Sonic hedgehog (Shh), an established polarizing signal protein during development, is expressed and functional in the adult human and murine stomach.


METHODS
Expression of Shh and putative transcriptional targets was investigated using immunoblot and immunohistochemistry. Mice were treated with the Shh inhibitor cyclopamine and examined for expression levels of Shh targets and proliferation of gastric epithelial cells.


RESULTS
Shh was expressed in the stomach. In cyclopamine-treated mice, we observed decreased expression of HNF3beta, Islet (Isl)-1 and BMP4, 3 putative Shh target genes. Inhibition of Shh markedly enhanced gastric epithelial proliferation and affected the cell cycle of gastric epithelial gland cells, whereas pit cells remained unaffected.


CONCLUSIONS
Shh controls the expression of at least 3 factors important for epithelial differentiation and is a negative regulator of gastric gland cell proliferation. Shh is a candidate polarizing signal in the maintenance of gastric pit-gland asymmetry.
van den Brink
G R
GR
Department of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. g.r.vandenbrink@amc.uva.nl
Hardwick
J C
JC
Tytgat
G N
GN
Brink
M A
MA
Ten Kate
F J
FJ
Van Deventer
S J
SJ
Peppelenbosch
M P
MP
D000367:Age Factors; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000032:analysis / Q000096:biosynthesis; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis; D004847:Epithelial Cells / Q000737:chemistry / Q000201:enzymology; D005753:Gastric Mucosa / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000032:analysis / Q000378:metabolism; D053823:Hedgehog Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D060850:LIM-Homeodomain Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis; D011506:Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013045:Species Specificity; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014704:Veratrum Alkaloids / Q000494:pharmacology
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014704:Veratrum Alkaloids; C063843:insulin gene enhancer binding protein Isl-1; D051542:Hepatocyte Nuclear Factor 3-beta; D017506:H(+)-K(+)-Exchanging ATPase; C000541:cyclopamine