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Secreted phosphoprotein 1 is a determinant of lung function development in mice.
Am. J. Respir. Cell Mol. Biol. 51, 637-651 (2014)
Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day 14-28) as compared to C3H/HeJ mice. In addition to a previously identified genetic variant that altered runt related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose dependent MLE-15 cell proliferation. Spp1((-/-)) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (Lm) compared to Spp1((+/+)) mice. Microarray analysis revealed enriched gene ontogeny (GO) categories with numerous genes associated with lung development and/or respiratory disease. IGF1, HHIP, WNT5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1((-/-)) mice as determined by qRT-PCR analysis. SPP1 promotes pneumocyte growth and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (increased Lm). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene targeted Spp1((-/-)) mice particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Asthma ; Chronic Obstructive Pulmonary Disease ; Emphysema ; Osteopontin ; Pulmonary Fibrosis; Obstructive Pulmonary-disease; Systemic-lupus-erythematosus; Superoxide-dismutase 3; Large Gene Lists; Branching Morphogenesis; Transcription Factor; Bronchopulmonary Dysplasia; Missing Heritability; Epithelial-cells; Heme Oxygenase-1
ISSN (print) / ISBN
1044-1549
e-ISSN
1535-4989
Quellenangaben
Volume: 51,
Issue: 5,
Pages: 637-651
Publisher
American Thoracic Society
Publishing Place
New York
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Epidemiology (EPI)