title: Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms.
abstract: During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1(-/-) mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1(-/-) mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1(-/-) mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development.
authors.affiliation: Department of Biochemistry &Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Antony
authors.affiliation: Department of Biochemistry &Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia.|The Hudson Institute of Medical Research, Clayton, 3168, Victoria, Australia.
authors.forename: A R
authors.initials: AR
authors.lastname: McDougall
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, 3010, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Mantamadiotis
authors.affiliation: Department of Biochemistry &Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Cole
authors.affiliation: Department of Biochemistry &Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia.
authors.forename: A D
authors.initials: AD
authors.lastname: Bird
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D003964:Diaphragm / Q000196:embryology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D017353:Gene Deletion; D005938:Glucocorticoids / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D010641:Phenotype; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D015415:Biomarkers; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids