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 epithe lial-mesenchymal cell signaling, Here, we demonstrate a role for platelet-d erived growth factor-a (PDGF-A) and its receptor, PDGFR-alpha, in this proc ess. Mice lacking PDGF-A or PDGFR-alpha were found to develop an abnormal G I mucosal lining, including fewer and misshapen villi and loss of pericrypt al mesenchyme, Onset of villus morphogenesis correlated with the formation of clusters of PDGFR-alpha positive cells, 'villus clusters', which remaine d 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 pos itive mesenchymal cells, the formation of fewer villus clusters, and premat ure expression of smooth muscle actin (SMA) in the villus mesenchyme, We fo und that the villus clusters were postmitotic, expressed BMP-2 and BMP-4, a nd that their formation correlated with downregulated DNA synthesis in adja cent intestinal epithelium. We propose a model in which villus morphogenesi s is initiated as a result of aggregation of PDGFR-alpha positive cells int o cell clusters that subsequently function as mesenchymal centers of signal ing 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.