Cyld encodes a 956-amino acid deubiquitinating enzyme (CYLD), which is a 
negative regulator of nuclear factor kappaB and mitogen-activated protein kinase 
pathways. Mutations that truncate and inactivate the carboxyl-terminal 
deubiquitinating domain of CYLD underlie the development of skin appendage 
tumors in humans, whereas down-regulation of Cyld expression has been associated 
with the development of various types of human malignancies including lung 
cancer. To establish an animal model of human CYLD inactivation and characterize 
the biological role of CYLD in vivo, we generated mice carrying a homozygous 
deletion of Cyld exon 9 (Cyld(Delta 9/Delta 9) mice) using a conditional 
approach. Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD 
and inactivation of its deubiquitinating activity. In accordance with previous 
studies, fibroblasts from Cyld(Delta 9/Delta 9) embryos had hyperactive nuclear 
factor kappaB and c-Jun kinase pathways compared with control fibroblasts. 
Cyld(Delta 9/Delta 9) newborn mice were smaller than wild-type littermates with 
a short and kinky tail and no major developmental defects. However, Cyld(Delta 
9/Delta 9) mice died shortly after birth from apparent respiratory dysfunction. 
Histological examination of E18.5 Cyld(Delta 9/Delta 9) lungs demonstrated an 
immature phenotype characterized by hyperplasic mesenchyme but apparently normal 
epithelial, smooth muscle. and endothelial structures. Our study identifies an 
important role of CYLD in lung maturation, which may underlie the development of 
many cases of lung cancer.