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Respiratory lethality in newborn NPAS3‐deficient mice
Author(s) -
Zhou Shutang,
Degan Simone,
Sunday Mary E
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.47.1
Subject(s) - bronchopulmonary dysplasia , lung , phenotype , immunostaining , sonic hedgehog , respiratory distress , biology , respiratory system , pathology , fetus , medicine , microbiology and biotechnology , anatomy , signal transduction , immunohistochemistry , gene , pregnancy , genetics , gestational age , anesthesia
The neuronal PAS domain protein 3 (NPAS3) is a close homolog of Drosophila Trachealess. By quantitative RT‐PCR, NPAS3 gene expression is highest at E10.5‐E13.5 in developing murine lungs. NPAS3 immunostaining shows positive nuclei in the developing mesenchyme and epithelium. NPAS3 loss‐of‐function embryos (KOs) have deficient lung branching. More than 95% of NPAS3 KO newborns die within 48 hours after birth in respiratory distress with poorly developed alveoli, abnormal distribution of smooth muscle actin along the airways and an increase in intrapulmonary nerve fibers. NPAS3 Heterozygotes (NPAS3‐Hets) have reduced alveolarization at birth as well, which persists in adults. The 4‐month old NPAS3‐Hets show airway hyperreactivity (AHR). Similarly, reduced alveolarization and AHR occur in premature infants with chronic lung disease, called bronchopulmonary dysplasia (BPD). Microarrays and QRT‐PCR demonstrate significantly decreased expression of sonic hedgehog (SHH), Gli2, FGF9, and BMP4 as well as elevated expression of Sprouty2 in NPAS3 KOs. Deficits in any or all of these signaling pathways could contribute to the observed pulmonary lethal phenotype in NPAS3 KOs. Our data suggest that NPAS3 play an important role in lung development and in responses to lung injury. Supported by NIH Grant HL44984.