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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/L777    most recent 00293.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by van Tuyl, M. Articles by Post, M. Search for Related Content PubMed PubMed Citation Articles by van Tuyl, M. Articles by Post, M.

Iroquois genes influence proximo-distal morphogenesis during rat lung development

¹Lung Biology Program, Hospital for Sick Children Research Institute, Toronto; Departments of ²Pediatrics and ³Physiology, University of Toronto, Toronto, Canada; and ⁴Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

Submitted 6 July 2005 ; accepted in final form 9 November 2005

Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1–3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in -tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gli₂-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.

Iroquois homeobox genes; differentiation; sonic hedgehog; fibroblast growth factor; bone morphogenic protein 4

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