Gastroenterology

Gastroenterology

Volume 121, Issue 2, August 2001, Pages 317-328
Gastroenterology

Alimentary Tract
Sonic hedgehog regulates gastric gland morphogenesis in man and mouse

https://doi.org/10.1053/gast.2001.26261Get rights and content

Abstract

Background & Aims: 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 HNF3β, 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.

GASTROENTEROLOGY 2001;121:317-328

Section snippets

Antibodies

The antibodies used are listed below.A goat polyclonal anti-Shh raised against and affinity-purified with Escherichia coli–derived recombinant mouse Shh N-terminal peptide (immunoblot, 1:1000), a mouse monoclonal anti–bone morphogenetic protein (BMP) 2 (monoclonal antibody [mAb] 355; immunohistochemistry, 1:1000; immunoblot, 1:2000), and a mouse monoclonal anti-BMP4 (mAb 757; immunohistochemistry, 1:500; immunoblot, 1:2000) were obtained from R&D systems (Minneapolis, MN).A goat polyclonal

Shh expression in the adult murine and human stomach

The continuing regeneration of the adult gastric glands is a process with 2 compartments and several gradients.We investigated whether the Shh signal protein, involved in many patterning processes during development, is expressed in this system.The small intestine, as a model of an intestinal linear differentiation process, was used for comparison.As shown in Figure 2, both Shh precursor protein (Figure 2A) and large amounts of the cleaved amino-terminal protein (Figure 2B) are present in the

Discussion

The mechanisms that maintain intricate patterns of differentiation in the adult organism have been given little consideration.We set out to investigate whether the signaling modules used during morphogenesis of the stomach remain active in morphostasis throughout life.Here it is shown that Shh may play a role in this process in the human and murine gastric epithelium.A first indication of active Shh signaling is the expression of Shh itself and Ptc, BMP2, BMP4, and HNF3β, 4 established

Acknowledgements

The authors thank Dr.W.Gaffield for the generous gift of the cyclopamine; Dr.R.Töftgard for donating the anti-Ptc antiserum; and J.Daalhuisen and A.Maas for expert technical assistance.

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    Address requests for reprints to: Gijs R.van den Brink, M.D., Laboratory of Experimental Internal Medicine, Room G2-130, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.e-mail: [email protected]; fax: (31) 20-6977192.

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