Am. J. Respir. Cell Mol. Biol., Volume 22, Number 4, April, 2000 451-459

A Novel Karyopherin- Homolog Is Developmentally and Hormonally Regulated in Fetal Lung

Chengdong Zhang, Neil B. Sweezey, Stéphane Gagnon, Brenda Muskat, David Koehler, Martin Post, and Feige Kaplan

Departments of Human Genetics and Pediatrics, and Montreal Children's Hospital Research Institute, McGill University, Montreal, Quebec; Departments of Paediatrics and Physiology, University of Toronto; Lung Biology Research, Research Institute; and Bioinformatics Supercomputing Centre, The Hospital for Sick Children, Toronto, Ontario, Canada

To investigate molecular mechanisms of lung organogenesis, we used representational difference analysis to search for glucocorticoid-inducible genes in developing lung in a fetal rat model. Messenger RNA prepared from fetal and adult rat lung was used to prepare "representative amplicons." Adult-lung complementary DNA (cDNA) amplicons were used as "driver" in successive rounds of subtractive hybridization/amplification to isolate target fetal lung-specific cDNAs. A single clone, which was conserved and had near-perfect homology to eight human/rodent expressed sequence tags, was used as template for 5' and 3' rapid amplification of cDNA ends and SPICE (system for polymerase chain reaction amplification of cDNA ends) reactions to obtain the 3.6-kb cDNA, LGL2 (Genbank, AF 110195) encoding a deduced polypeptide (lgl2) of 963 amino acids. Northern analysis confirmed that LGL2 is differentially expressed in fetal lung (maximal during the pseudoglandular stage, gestational Days 14 to 16), induced by glucocorticoid, and enriched in epithelium relative to the mesenchyme. LGL2 was also detected in human fetal lung at gestational Week 16 as well as in human and rat fetal brain, heart, intestine, and kidney. We mapped LGL2 to chromosome 1p33-34.2. Comparison with sequences in the genome database identified lgl2 as a member of the karyopherin- family of nuclear import proteins, with greatest homology to transportin SR. Maximal expression of LGL2 in the pseudoglandular stage of development is coordinate with that of key transcription factors that regulate prominent signal transduction pathways in fetal lung organogenesis. We propose a role for lgl2 in nuclear import of transcription factors that regulate signal transduction during fetal lung development.

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