Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis.
Development of the gastrointestinal (GI) tract depends on reciprocal epithelial-mesenchymal cell signaling. Here, we demonstrate a role for platelet-derived growth factor-A (PDGF-A) and its receptor, PDGFR-(alpha), in this process. Mice lacking PDGF-A or PDGFR-(alpha) were found to develop an abnormal GI mucosal lining, including fewer and misshapen villi and loss of pericryptal mesenchyme. Onset of villus morphogenesis correlated with the formation of clusters of PDGFR-(alpha) positive cells, 'villus clusters', which remained located at the tip of the mesenchymal core of the growing villus. Lack of PDGF-A or PDGFR-(alpha) resulted in progressive depletion of PDGFR-(alpha) positive mesenchymal cells, the formation of fewer villus clusters, and premature expression of smooth muscle actin (SMA) in the villus mesenchyme. We found that the villus clusters were postmitotic, expressed BMP-2 and BMP-4, and that their formation correlated with downregulated DNA synthesis in adjacent intestinal epithelium. We propose a model in which villus morphogenesis is initiated as a result of aggregation of PDGFR-(&agr;) positive cells into cell clusters that subsequently function as mesenchymal centers of signaling to the epithelium. The role of PDGF-A seems to be to secure renewal of PDGFR-(alpha) positive cells when they are consumed in the initial rounds of cluster formation.
Karlsson
L
L
Department of Medical Biochemistry, Göteborg University, Medicinaregatan 9A, Box 440, SE 405 30 Göteborg, Sweden. Linda. Karlsson@medkem.gu.se
Lindahl
P
P
Heath
J K
JK
Betsholtz
C
C
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002454:Cell Differentiation; D002455:Cell Division; D004064:Digestive System / Q000196:embryology; D020869:Gene Expression Profiling; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology*; D008648:Mesoderm; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008871:Microvilli; D009024:Morphogenesis; D009130:Muscle, Smooth / Q000166:cytology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000502:physiology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha