Lgl1, a mesenchymal modulator of early lung branching morphogenesis, is a secreted glycoprotein imported by late gestation lung epithelial cells.
Secreted glycoproteins serve a variety of functions related to cell-cell communication in developmental systems. We cloned LGL1, a novel glucocorticoid-inducible gene in foetal lung, and described its temporal and spatial localization in the rat. Disruption of foetal mesenchyme-specific LGL1 expression using antisense oligodeoxynucleotides, which was associated with a 50% decrease in lgl1 protein levels, inhibited airway epithelial branching in foetal rat gestational day 13 lung buds in explant culture. These findings suggested that lgl1 functions as a secreted signalling molecule. We now provide evidence supporting a role for lgl1 in mesenchymal-epithelial interactions that govern lung organogenesis. Lgl1 is a secreted glycoprotein with a conserved N-terminal secretory signal peptide. Using dual immunofluorescence, intracellular lgl1 was found to co-localize with markers of the Golgi apparatus and endoplasmic reticulum, consistent with its association with secretory vesicles. Using pulse-chase studies, we show that lgl1 is a stable protein with a half-life of 11.5 h. Furthermore, at gestational days 20 and 21 (term=22), foetal distal lung epithelial cells import lgl1 protein. Taken together, our findings support distinct roles for lgl1 as a mediator of glucocorticoid-induced mesenchymal-epithelial interactions in early and late foetal lung organogenesis.
Oyewumi
Lami
L
Lung Biology Research, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Kaplan
Feige
F
Sweezey
Neil B
NB
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000737:chemistry; D004847:Epithelial Cells / Q000378:metabolism; D005865:Gestational Age; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000737:chemistry; D006801:Humans; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000502:physiology; D009024:Morphogenesis; D021382:Protein Sorting Signals; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000196:embryology* / Q000378:metabolism
C120070:CrispId2 protein, rat; D006023:Glycoproteins; D021382:Protein Sorting Signals; D011506:Proteins