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

Abstract

The proximal-distal patterning of lung epithelium involves a complex series of signaling and transcriptional events resulting in the programmed differentiation of highly specialized cells for gas exchange and surfactant protein expression essential for postnatal lung function. The BMP signaling pathway 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 BMP antagonists, including gremlin, cer-1, PRDC, and Dan are expressed in the lung during embryonic development with gremlin expression observed in the proximal airway epithelium. The role of gremlin in lung development was explored by overexpressing it in the distal lung epithelium of transgenic mice 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 mammalian lung. Expanded expression of the proximal epithelial cell markers CC10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lungs. Furthermore, smooth muscle ␣-actin expression was observed surrounding the distal airways of SP-C/gremlin mice, indicating a proximalization of distal lung tubules. These data suggest that gremlin plays an important role in lung morphogenesis by regulating the proximal-distal patterning of the lung during development.

Expression of the protein related to Dan and Cerberus gene—prdc—During eye, pharyngeal arch, somite, and swim bladder development in zebrafish

“…DAN knockout mice have only subtle defects (Dionne et al, 2001). In contrast, Gremlin-deficient mice display abnormal lung, kidney, and limb development, and Gremlin overexpression interferes with the proximaldistal patterning in lung morphogenesis (Lu et al, 2001;Shi et al, 2001;Khokha et al, 2003;Michos et al, 2004). Collectively, the expression studies and the gain-and loss-of-function data across species infer critical roles of the DAN family during development, also suggesting operational redundancies among different antagonists (Khokha et al, 2005).…”

“…The swim bladder in fish is the anatomic ancestor of the lung in terrestrial species. Thus, the observed prdc expression in the zebrafish swim bladder-predating the mouse lung mesenchyme expression (Lu et al, 2001)-is highly conserved in evolution. At late time points, e.g., 72 hpf, expression also appears in the layer of the oral epithelium (Fig.…”

“…In mice, Prdc is expressed in lung mesenchyme, together with the closely related Gremlin 1 gene (Lu et al, 2001). Prdc has been also localized to commissural neurons of the developing spinal cord in mice (Minabe-Saegusa et al, 1998).…”

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

“…However, additional signalling pathways are acknowledged to play important roles in malignant disease, with the bone morphogenetic protein (BMP) signalling pathway emerging as important in multiple cancers (Nagatake et al, 1996;Tamada et al, 2001;Baldus et al, 2004;Dai et al, 2004;Kim et al, 2004). It is well recognised that the BMP signalling pathways are crucial for all stages of embryonic development, including regulation of lung development and airway branching (Weaver et al, 1999;Lu et al, 2001;Rosendahl et al, 2002). The BMPs have been shown to be growth inhibitory by suppressing proliferation (Dai et al, 2004;Haudenschild et al, 2004).…”

Lung Stem/Progenitor Cells: Regulatory Mechanisms of Behavior, Development and Regeneration

“…This is supported by several studies showing that inactivation of Bmp signaling by overexpression of a dominant-negative Bmp receptor, or the Bmp antagonists Gremlin or Noggin results in proximalization of the lung epithelium [95,96]. These lung proximalization phenotypes can result from a reduction of Bmp or Wnt signaling [80,81].…”