Epithelial inactivation of Yy1 abrogates lung branching morphogenesis.
Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation whereas Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be partly explained by the reduced expression of Shh, a transcriptional target of YY1, in lung endoderm, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Olivier
O
Boucherat
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Kim
K
Landry-Truchon
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Félix-Antoine
FA
Bérubé-Simard
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Nicolas
N
Houde
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Laurent
L
Beuret
AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Université Paris-Descartes, Paris, 75015, France Inserm U955, IMRB, Equipe 04, Créteil, 94011, France.
Guillaume
G
Lezmi
Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montréal, H3G 1A4, Canada.
William D
WD
Foulkes
AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Université Paris-Descartes, Paris, 75015, France Inserm U955, IMRB, Equipe 04, Créteil, 94011, France.
Christophe
C
Delacourt
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada.
Jean
J
Charron
Centre de Recherche sur le Cancer de l'Université Laval; CRCHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 3S3, Canada lucie.jeannotte@crhdq.ulaval.ca.
Lucie
L
Jeannotte
D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D002356:Cartilage / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D004707:Endoderm / Q000196:embryology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism*; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000196:embryology* / Q000378:metabolism*; D008171:Lung Diseases / Q000151:congenital / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009024:Morphogenesis; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058628:Myofibroblasts / Q000473:pathology; D010641:Phenotype; D018202:Pulmonary Blastoma / Q000378:metabolism / Q000473:pathology; D043244:Ribonuclease III / Q000378:metabolism; D014132:Trachea / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D050986:YY1 Transcription Factor / Q000378:metabolism*
D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C494699:Yy1 protein, mouse; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
DICER1; FGF10; Lung branching; Pleuropulmonary blastoma; SHH; YY1