The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung

The proximal-distal patterning of lung epithelium involves a complex series of signaling and transcriptional events resulting in the programmed differ entiation of highly specialized cells for gas exchange and surfactant prote in expression essential for postnatal lung function. The BMP signaling path way has been shown to regulate cellular differentiation in the lung as well as other tissues. In this report, we show that the can family of related B MP antagonists, including gremlin, cer-1, PRDC, and Dan are expressed in th e lung during embryonic development with gremlin expression observed in the proximal airway epithelium. The role of gremlin in lung development was ex plored by overexpressing it in the distal. lung epithelium of transgenic mi ce using the human SP-C promoter. SP-C/gremlin transgenic mice exhibited a disruption of the proximal-distal patterning found in the airways of the ma mmalian lung. Expanded expression of the proximal epithelial cell markers C C10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lung s. Furthermore, smooth muscle alpha -actin expression was observed surround ing the distal airways of SP-C/gremlin mice, indicating a proximalization o f distal lung tubules. These data suggest that gremlin plays an important r ole in lung morphogenesis by regulating the proximal-distal patterning of t he lung during development. (C) 2001 Wiley-Liss, Inc.