Operational parallels in overall mechanisms of three-dimensional patterning of vertebrate organs are becoming increasingly apparent. Many key mediators, such as FGFs, BMPs, and sonic hedgehog, participate in organization of a number of organs, including the lungs, which exhibit a defined proximodistal (P-D) polarity. Recently, Wnt5a a member of the wingless family of signaling molecules involved in cell proliferation, differentiation, and organogenesis, was shown to underlie the outgrowth and P-D morphogenesis of the vertebrate limb. In the current study, we show that Wnt5a is expressed in the mouse lung and plays an important role in lung distal morphogenesis. Analysis of the mutant phenotype in mice carrying a targeted disruption of the Wnt5a locus shows distinct abnormalities in distal lung morphogenesis as manifested by distinct truncation of the trachea and overexpansion of the distal respiratory airways. In the face of deleted WNT5a activity, both epithelial and mesenchymal cell compartments of the Wnt5a(-/-) lungs exhibit increased cell proliferation. The overall architecture of the mutant lungs is characterized by overexpansion of the distal airways and inhibition of lung maturation as reflected by persistence of thickened intersaccular interstitium. Absence of WNT5a activity in the mutant lungs leads to increased expression of Fgf-10, Bmp4, Shh, and its receptor Ptc, raising the possibility that WNT5a, FGF-10, BMP4, and SHH signaling pathways are functionally interactive.

The strong expression of leptin, in amniotic fluid when fetuses begin swallowing then in the gastric mucosa, and the early presence of Ob-Rb in mucosae suggest a possible role for leptin, exerted endoluminally and in a paracrine pathway, in the developmental process (growth and/or maturation) of the human digestive tract.

Transforming growth factor-alpha (TGF-alpha) is overexpressed in colonic carcinomas and promotes mucosal wound healing. It may be implicated in chronic inflammatory bowel disease (IBD). We analyzed the expression of TGF-alpha and its receptor, epidermal growth factor receptor (EGF-r), in the colonic mucosa of patients with Crohn's disease (CD) or ulcerative colitis (UC), in active or inactive stages, as compared with controls. Proteins and mRNA were detected in biopsies from the right and left colon and in surgical colonic specimens. Immunoblot analysis revealed TGF-alpha protein as a 29 kDa band. This band was normally expressed in uninvolved colonic mucosa of patients with CD or UC whether in active or inactive stages, but decreased or absent in involved mucosa of active IBD, even when TGF-alpha mRNA and EGF-r protein were detected. In the unaffected mucosa of CD, the intensity of TGF-alpha immunoreactivity was similar to that of controls in the right colon but stronger (P = 0.05) in the left colon. There was no TGF-alpha overexpression in dysplastic regions. In conclusion, in active IBD disease, the decreased TGF-alpha protein amount seems not only related to epithelial cell loss but reflects a down-regulation at least at the protein level. We speculate that TGF-alpha does not play a role within the active stage but may be implicated later in the repair process.

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This study was designed to localize transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-alpha and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-alpha and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-alpha in the esophagus. The strongest TGF-alpha immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagonsecreting cells were shown to express TGF-alpha, while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-alpha and its receptor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-alpha during the developmental process of the digestive system. We demonstrate that TGF-alpha is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life.

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Background-The role that exogenous transforming growth factor-a (TGF-ox) may exert on cell proliferation in vivo is poorly understood. Aim-To investigate the effect of rat TGF-a on epithelial cell proliferation in all suckling rat digestive tissues and to compare it with that of rat epidermal growth factor (EGF). Animals and Methods-TGF-a and EGF were given three times daily either subcutaneously (10 or 20 jiglkg) or intraperitoneally (100 ,ug/kg) to rats from the ninth postnatal day. Cell proliferation was assessed through 5-bromo-2-deoxyuridine incorporation and estimation of labelling indices. Results-For both growth factors, the highest dose given for only two days significantly increased stomach and intestinal weights compared with controls (p<005 to p<0-001). The proliferative responses depended on the dose given, colonic mucosa being the most sensitive whereas oxyntic mucosa remained unresponsive. TGF-a was as potent as EGF in stimulating epithelial cell proliferation in antral, duodenal, and colonic mucosae. However, EGF was more active on oesophageal and jejunal cell proliferation whereas TGF-at was more active on pancreatic exocrine cell proliferation and the differences between the two growth factor treated groups were significant. Conclusions-These results prove for the first time the stimulating effect in vivo of exogenous rat TGF-a on epithelial cell proliferation in rat digestive tissues during the developmental period and support a functional role for TGF-ax at that time.

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