CFTR modulates lung secretory cell proliferation and differentiation.
We have permanently reversed the lethal phenotype in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-deficient (knockout) mouse after in utero gene therapy with an adenovirus containing the cftr gene. The gene transfer targeted somatic stem cells in the developing lung and intestine, and these epithelial surfaces demonstrated permanent developmental changes after treatment. The survival statistics from the progeny of heterozygote-heterozygote matings after in utero cftr gene treatment demonstrated an increased mortality in the homozygous normal pups, indicating that overexpression during development was detrimental. The lungs of these pups revealed accelerated secretory cell proliferation and differentiation. The extent of proliferation and differentiation in the secretory cells of the lung parenchyma after in utero transfer of the cftr gene was evaluated with morphometric and biochemical analyses. These studies provide further support of the regulatory role of the cftr gene in the development of the secretory epithelium.
Larson
J E
JE
Laboratory of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans 70121, USA. janlarson@hotmail.com
Delcarpio
J B
JB
Farberman
M M
MM
Morrow
S L
SL
Cohen
J C
JC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005315:Fetal Diseases / Q000235:genetics / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D007422:Intestines / Q000737:chemistry / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000196:embryology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D015996:Survival Rate
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA