Prenatal Lung Epithelial Cell-Specific Abrogation of Alk3-Bone Morphogenetic Protein Signaling Causes Neonatal Respiratory Distress by Disrupting Distal Airway Formation

Abstract

Bone morphogenetic proteins (BMPs) play important roles in regulating lung development and function although the endogenous regulatory effects of BMP signaling are still controversial. We found that BMP type I receptor Alk3 is expressed predominantly in airway epithelial cells during development. The function of Alk3 in lung development was determined using an inducible knockout mouse model by crossing epithelial cell-specific Cre transgenic mice SPC-rtTA/TetO-Cre and floxed-Alk3 mice. Abrogation of Alk3 in mouse lung epithelia from either early lung organogenesis or late gestation resulted in similar neonatal respiratory distress phenotypes accompanied by collapsed lungs. Early-induction of Alk3 knockout in lung epithelial cells caused retardation of early lung branching morphogenesis, reduced cell proliferation, and differentiation. However, late gestation induction of the knockout caused changes in cell proliferation and survival, as shown by altered cell biology, reduced expression of peripheral epithelial markers (Clara cell-specific protein, surfactant protein C, and aquaporin-5), and lack of surfactant secretion. Furthermore, canonical Wnt signaling was perturbed, possibly through reduced Wnt inhibitory factor-1 expression in Alk3-knockout lungs. Therefore, our data suggest that deficiency of appropriate BMP signaling in lung epithelial cells results in prenatal lung malformation, neonatal atelectasis, and respiratory failure.

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

“…57 Taken together, these findings strongly suggest that aberrations in BMP/TGF-␤-related signaling pathways cause or contribute to BPD in premature infants and PPD seen in survivors. A better understanding of how aberrations in BMP/TGF-␤ signaling contribute to lung disease might lead to novel treatment regimens.…”

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

“…The murine model used by these authors demonstrates that changes in BMP signaling subsequently cause respiratory distress syndrome in the early postnatal period. Analysis of the lung tissue of activin-like kinase 3 conditional knockout mice has demonstrated that decreased BMP signaling is associated with increased canonical Wnt signaling, as evidenced by increased phosphorylation of the Wnt coreceptor low-density lipoprotein receptor-related protein 6 and activation of downstream β-catenin (Sun et al, 2008).…”

“…Decreased WIF1 expression in human disease states, including lung cancer, has been related to hypermethylation of the promoter region of the gene (Ai et al, 2006). Sun et al (2008) have previously shown that abrogation of activin-like kinase 3-mediated bone morphogenetic protein (BMP) signaling in lung epithelial cells during early lung development disrupts cell differentiation and proliferation, resulting in abnormal lung branching morphogenesis. The murine model used by these authors demonstrates that changes in BMP signaling subsequently cause respiratory distress syndrome in the early postnatal period.…”

Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development

“…Transmission electron microscopy (TEM) was performed on E18.5 lung tissues as previously described (Sun et al, 2008). Ultrathin sections stained with uranyl acetate and lead citrate were viewed and photographed under a JEOL 1200CX electron microscope.…”

“…In addition, Smad-independent pathways have also been reported to transduce BMP signals (Derynck and Zhang, 2003). Previous studies by us and other groups have found that Alk3 [also known as BMP type IA receptor (Bmpr1a)], rather than Alk2 (Acvr1) and Alk6 (Bmpr1b), plays an essential role in mediating BMP regulatory signals during prenatal lung development in mice (Eblaghie et al, 2006;Sun et al, 2008). Abrogation of Alk3 in developing mouse lung epithelial cells causes immediate neonatal respiratory distress and lethality due to abnormal fetal lung formation and postnatal lung atelectasis.…”