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Hoxb-5 control of early airway formation during branching morphogenesis in the developing mouse lung
Authors:MaryAnn V Volpe  Robert J Vosatka  Heber C Nielsen
Institution:1. Department of Pediatrics, Division of Newborn Medicine, The Floating Hospital for Children at New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Box # 44, Boston, MA 02111, USA;2. Department of Pediatrics, Division of Newborn Medicine, Columbia University, New York, NY, USA
Abstract:Hox proteins control structural morphogenesis, pattern formation and cell fate in the developing embryo. To determine if Hoxb-5 participates in patterning of early airway branching during lung morphogenesis, gestational day 11.5 embryonic lung cultures were treated with retinoic acid (RA) to up-regulate and antisense oligonucleotides to down-regulate Hoxb-5 protein expression. RA (10?6 M) and Hoxb-5 antisense oligonucleotide (20 μM) treatment each significantly decreased branching morphogenesis (P<0.001), but the morphology of branching under these conditions was very different. RA-treated lungs had elongated primary branches but decreased further branching with increased Hoxb-5 immunostaining in subepithelial regions underlying these elongated airways. Western blots confirmed that Hoxb-5 protein was increased by 189±20% (mean±S.E.M., P<0.05) in RA-treated lungs compared to controls. In contrast, lungs treated with Hoxb-5 antisense oligos plus RA had foreshortened primary branches with rudimentary distal clefts resulting in decreased numbers of primary and subsequent branches. Immunohistochemistry confirmed that Hoxb-5 antisense oligos inhibited Hoxb-5 protein expression even in the presence of RA. We conclude that regional and quantitative changes in Hoxb-5 protein expression influence morphogenesis of the first airway divisions from the mainstem bronchi. RA-induced alterations in branching are mediated in part through regulated Hoxb-5 expression.
Keywords:Homeobox gene  Hoxb-5  Retinoic acid  Antisense oligonucleotide  Lung development  Branching morphogenesis
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