l7Rn6 Encodes a Novel Protein Required for Clara Cell Function in Mouse Lung Development

Rodrigo Fernández-Valdivia^*^,1, Ying Zhang^*, Sonia Pai^*, Michael L. Metzker^*^, and Armin Schumacher^*^,2

^* Department of Molecular and Human Genetics and Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030

^² Corresponding author: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, S-803, Houston, TX 77030.
E-mail: armins{at}bcm.tmc.edu

The highly secretory Clara cells play a pivotal role in protectingthe lung against inflammation and oxidative stress. This studyreports the positional cloning of a novel protein required forClara cell physiology in mouse lung development. The perinatallethal N-ethyl-N-nitrosourea-induced l7Rn6^4234SB allele containeda nonsense mutation in the previously hypothetical gene NM_026304on chromosome 7. Whereas l7Rn6 mRNA levels were indistinguishablefrom wild type, l7Rn6^4234SB homozygotes exhibited decreasedexpression of the truncated protein, suggesting protein instability.During late gestation, l7Rn6 was widely expressed in the cytoplasmof lung epithelial cells, whereas perinatal expression was restrictedto the bronchiolar epithelium. Homozygosity for the l7Rn6^4234SBallele did not affect early steps in lung patterning, growth,or cellular differentiation. Rather, mutant lungs demonstratedsevere emphysematous enlargement of the distal respiratory sacsat birth. Clara cell pathophysiology was evident from decreasedcytoplasmic CCSP and SP-B protein levels, enlargement and disorganizationof the Golgi complex, and formation of aberrant vesicular structures.Additional support for a role in the secretory pathway derivedfrom l7Rn6 localization to the endoplasmic reticulum. Thus,l7Rn6 represents a novel protein required for organization and/orfunction of the secretory apparatus in Clara cells in mouselung.