title: Temporal-spatial expression and transcriptional regulation of alpha7 nicotinic acetylcholine receptor by thyroid transcription factor-1 and early growth response factor-1 during murine lung development.
abstract: Nicotinic acetylcholine receptors are ligand-gated ion channels formed by five homologous subunits that are involved in processes including signal transduction, proliferation, and apoptosis. The developmental role of these receptors, however, is unclear. In the present investigation, alpha(7) nicotinic acetylcholine receptor expression was assessed by immunohistochemistry in mouse lungs from embryonic day (E)13.5 to postnatal day (PN)20. Transcriptional mechanisms that regulate alpha(7) were assessed by the transfection of murine bronchiolar cells with a reporter containing 1.1 kb of the mouse alpha(7) promoter, TTF-1, and Egr-1. alpha(7) was initially detected at E13.5 in pulmonary mesenchymal cells and in the epithelium of the primitive tubules at E15.5. From E18.5 to PN1, alpha(7) was expressed in conducting airway and saccule epithelial cells. By PN10, expression was observed in the peripheral epithelium and on luminal membranes of bronchiolar epithelial cells in the proximal lung, a pattern that continued through PN20. From E15.5 to PN20, type II alveolar cells expressed both prosurfactant protein C and alpha(7). From E18.5 to PN20, Clara cells in the bronchiolar epithelium co-expressed Clara cell secretory protein and alpha(7). TTF-1 dose-dependently activated alpha(7) transcription in vitro by binding specific TTF-1 regulatory elements in the mouse alpha(7) promoter. Furthermore, alpha(7) was not detected in TTF-1-null mice and markedly increased in TTF-1-overexpressing mice. Conversely, Egr-1 inhibited alpha(7) expression. Temporal-spatial alpha(7) expression supports the concept that these receptors function during normal pulmonary morphogenesis. A model is also supported whereby alpha(7) is induced by the essential pulmonary transcription factor TTF-1 and suppressed by Egr-1 during pulmonary development.
authors: Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, 84132, USA.
authors: Paul R
authors: PR
authors: Reynolds
authors: John R
authors: JR
authors: Hoidal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D051766:Early Growth Response Protein 1; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D000074482:Thyroid Nuclear Factor 1; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000911:Antibodies, Monoclonal; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D037721:Pulmonary Surfactant-Associated Protein C; D011978:Receptors, Nicotinic; C504003:TTF1 protein, human; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor