title: Abrogation of Eya1/Six1 disrupts the saccular phase of lung morphogenesis and causes remodeling.
abstract: The Eya1 gene encodes a transcriptional co-activator that acts with Six1 to control the development of different organs. However, Six1-Eya1 interactions and functional roles in mesenchymal cell proliferation and differentiation as well as alveolarization during the saccular stage of lung development are still unknown. Herein, we provide the first evidence that Six1 and Eya1 act together to regulate mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis. Deletion of either or both Six1 and Eya1 genes results in a severe saccular phenotype, including defects of mesenchymal cell development and remodeling of the distal lung septae and arteries. Mutant lung histology at the saccular phase shows mesenchymal and saccular wall thickening, and abnormal proliferation of α-smooth muscle actin-positive cells, as well as increased mesenchymal/fibroblast cell differentiation, which become more sever when deleting both genes. Our study indicates that SHH but not TGF-β signaling pathway is a central mediator for the histologic alterations described in the saccular phenotype of Eya1(-/-) or Six1(-/-) lungs. Indeed, genetic reduction of SHH activity in vivo or inhibition of its activity in vitro substantially rescues lung mesenchymal and alveolar phenotype of mutant mice at the saccular phase. These findings uncover novel functions for Six1-Eya1-SHH pathway during the saccular phase of lung morphogenesis, providing a conceptual framework for future mechanistic and translational studies in this area.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, CA 90027, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Lu
authors.forename: Raghava
authors.initials: R
authors.lastname: Reddy
authors.forename: Mohamed
authors.initials: M
authors.lastname: Berika
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Ahmed H K
authors.initials: AH
authors.lastname: El-Hashash
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C465570:Shh protein, mouse; C490947:Six1 protein, mouse; D014704:Veratrum Alkaloids; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases; C000541:cyclopamine
keywords: Eya1; Lung development; SHH; Saccular phase; Six1