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The Role of Mesenchymal BMP Signaling Pathway in the Lung Development
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A6966 - The Role of Mesenchymal BMP Signaling Pathway in the Lung Development
Author Block: Y. Luo1, W. Shi2, H. Chen3; 1Children hospital Los Angeles, Los Angeles, CA, United States, 2Childrens Hosp Los Angeles, Los Angeles, CA, United States, 3Children's Hospital Los Angeles, Los Angeles, CA, United States.
Background: Abnormal activation of BMP signaling in fetal lung epithelial cell results in lung malformation, in particular, defects in distal lung epithelial cell proliferation and differentiation/maturation. However, the role of BMP signaling in regulating fetal lung mesenchymal development and its association to congenital pulmonary abnormality remains unknown. Methods: BMP receptor 1a (Bmpr1a) flox mice were crossed with Tbx4-rtTA/TetO-Cre transgenic mice and received doxycycline treatment from E6.5 to generate the lung mesenchyme-specific and inducible Bmpr1a conditional knockout (CKO) mice. Specimens were harvested from E13.5 to E18.5. Results: Lung mesenchymal abrogation of Bmpr1a led to decreased activation of BMP signaling pathway specifically in mesenchyme as determined by reduced Smad1 phosphorylation. Bmpr1a CKO fetal lung developed congenital airway cysts mid-gestation, which are the characterized lesions of some subtypes of human congenital pulmonary airway malformation (CPAM). Bmpr1a CKO also disrupted the growth of airway smooth muscle cell that was found in the CPAM lungs. In addition, lung epithelial cell growth was impeded due to mesenchymal knockout of Bmpr1a, leading to inhibited cell proliferation and impaired cell differentiation. RNA sequencing showed that mesenchymal knockout of Bmpr1a and downregulation of BMP signaling resulted in aberrant expression of many BMP ligands including BMP2, BMP4 and BMP7 in the lung. Conclusion: BMP-Bmpr1a-mediated signaling in lung mesenchymal cells is essential to fetal lung development. Conditional knockout of Bmpr1a in lung mesenchyme substantially inhibits BMP signaling pathway, leading to congenital pulmonary cysts by disrupting airway smooth muscle and epithelial cell growth.
Author Block: Y. Luo1, W. Shi2, H. Chen3; 1Children hospital Los Angeles, Los Angeles, CA, United States, 2Childrens Hosp Los Angeles, Los Angeles, CA, United States, 3Children's Hospital Los Angeles, Los Angeles, CA, United States.
Background: Abnormal activation of BMP signaling in fetal lung epithelial cell results in lung malformation, in particular, defects in distal lung epithelial cell proliferation and differentiation/maturation. However, the role of BMP signaling in regulating fetal lung mesenchymal development and its association to congenital pulmonary abnormality remains unknown. Methods: BMP receptor 1a (Bmpr1a) flox mice were crossed with Tbx4-rtTA/TetO-Cre transgenic mice and received doxycycline treatment from E6.5 to generate the lung mesenchyme-specific and inducible Bmpr1a conditional knockout (CKO) mice. Specimens were harvested from E13.5 to E18.5. Results: Lung mesenchymal abrogation of Bmpr1a led to decreased activation of BMP signaling pathway specifically in mesenchyme as determined by reduced Smad1 phosphorylation. Bmpr1a CKO fetal lung developed congenital airway cysts mid-gestation, which are the characterized lesions of some subtypes of human congenital pulmonary airway malformation (CPAM). Bmpr1a CKO also disrupted the growth of airway smooth muscle cell that was found in the CPAM lungs. In addition, lung epithelial cell growth was impeded due to mesenchymal knockout of Bmpr1a, leading to inhibited cell proliferation and impaired cell differentiation. RNA sequencing showed that mesenchymal knockout of Bmpr1a and downregulation of BMP signaling resulted in aberrant expression of many BMP ligands including BMP2, BMP4 and BMP7 in the lung. Conclusion: BMP-Bmpr1a-mediated signaling in lung mesenchymal cells is essential to fetal lung development. Conditional knockout of Bmpr1a in lung mesenchyme substantially inhibits BMP signaling pathway, leading to congenital pulmonary cysts by disrupting airway smooth muscle and epithelial cell growth.
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