The lung arises from the foregut endoderm as an epithelial bud surrounded by mesodermal mesenchyme. Lung mesenchyme gives rise to the various lineages of pulmonary smooth muscle, including vascular smooth muscle cells (VSMCs) which are essential for blood vessel integrity. However, little is known of the molecular signaling processes that are involved in the specification and/or differentiation of VSMCs in the lung, although paracrine signaling from the endoderm has been shown to play an important rote. Proper development of the pulmonary vasculature is important in the development of the lung as a functional organ and defects in this process can lead to several human diseases including pulmonary hypertension. We have shown that inactivation of the Wnt7b gene, which is expressed in the developing airway epithelium, results in loss of vascular smooth muscle integrity in the lung, leading to perinatal hemorrhage and death. Since Wnt7b expression in the lung decreases in late gestation, we hypothesize that Wnt7b is required for proper development of VSMCs from lung mesenchyme through epithelial-mesenchymal signaling occurring early in lung development. In support of this hypothesis, we have found that the winged-helix transcription factor Foxf2, which is expressed in lung mesenchyme, is specifically down regulated in the lungs of Wnt7b/lacz-/- embryos. These results suggest that vascular smooth muscle development and integrity requires Wnt7b signaling, possibly by regulating genes such as Foxf2, which are required for proper development of VSCMs from lung mesenchyme. The goal of this proposal is to characterize the molecular mechanisms underlying Wnt7b regulation of VSMC development in the lung by addressing three questions: 1) Does Wnt7b act on definitive VSMCs or their precursors during lung vascular development?, 2) Does Wnt7b signal via canonical or non-canonical Wnt pathways in lung VMSC development and what are the global roles for these pathways in this process?, and 3) What are the down-stream effector pathways that Wnt7b influences to regulate VSMC differentiation and development? We expect that the results of these studies will lead to a better understanding of the mechanisms underlying vascular heterogeneity and, in particular, how Writ signaling regulates these developmental events.
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