title: l7Rn6 encodes a novel protein required for clara cell function in mouse lung development.
abstract: The highly secretory Clara cells play a pivotal role in protecting the lung against inflammation and oxidative stress. This study reports the positional cloning of a novel protein required for Clara cell physiology in mouse lung development. The perinatal lethal N-ethyl-N-nitrosourea-induced l7Rn6(4234SB) allele contained a nonsense mutation in the previously hypothetical gene NM_026304 on chromosome 7. Whereas l7Rn6 mRNA levels were indistinguishable from wild type, l7Rn6(4234SB) homozygotes exhibited decreased expression of the truncated protein, suggesting protein instability. During late gestation, l7Rn6 was widely expressed in the cytoplasm of lung epithelial cells, whereas perinatal expression was restricted to the bronchiolar epithelium. Homozygosity for the l7Rn6(4234SB) allele did not affect early steps in lung patterning, growth, or cellular differentiation. Rather, mutant lungs demonstrated severe emphysematous enlargement of the distal respiratory sacs at birth. Clara cell pathophysiology was evident from decreased cytoplasmic CCSP and SP-B protein levels, enlargement and disorganization of the Golgi complex, and formation of aberrant vesicular structures. Additional support for a role in the secretory pathway derived from l7Rn6 localization to the endoplasmic reticulum. Thus, l7Rn6 represents a novel protein required for organization and/or function of the secretory apparatus in Clara cells in mouse lung.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández-Valdivia
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sonia
authors.initials: S
authors.lastname: Pai
authors.forename: Michael L
authors.initials: ML
authors.lastname: Metzker
authors.forename: Armin
authors.initials: A
authors.lastname: Schumacher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006056:Golgi Apparatus / Q000648:ultrastructure; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D051379:Mice / Q000196:embryology* / Q000378:metabolism; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D014598:Uteroglobin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; D037701:Pulmonary Surfactant-Associated Protein B; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C509389:l7Rn6 protein, mouse; D014598:Uteroglobin; D010741:Phospholipases A; D005038:Ethylnitrosourea