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Gene expression in Mob1DKO mouse lung

ABSTRACT: Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumor Suppressor homolog (LATS) kinases, are also tumor suppressors. To investigate MOB1A/B’s roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium–specific, null mutations of MOB1A/B in mice [SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO) mice]. Most mutants (70%) receiving Dox in utero [luMob1DKO (E6.5-18.5) mice] died of hypoxia within 1hr post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation, and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome　(RDS). Intriguingly, mutant mice that received Dox postnatally [luMob1DKO (P21–41) mice] did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumor formation was decreased (rather than increased). Lungs of luMob1DKO (P21–41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells (BASCs) thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE93778 | GEO | 2017/03/29

SECONDARY ACCESSION(S): PRJNA362351

REPOSITORIES: GEO

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Project description:Nkx2.1 is a critical regulator of mammalian lung development. It is expressed in epithelial cells at the initiation of lung organogenesis, becoming progressively restricted during development to bronchiolar and alveolar type II epithelial cells. In humans, it is a common marker of carcinomas of lung and thyroid origin and is highly amplified in 10-15% of lung adenocarcinomas. Despite its key role in development and disease only a few genes directly regulated by Nkx2.1 are known. To identify direct Nkx2.1target genes and pathways controlled by this transcription factor in vivo we analyzed, by chromatin immuno-precipitation (chip)-on-chip method, Nkx2.1 binding to DNA cis-elements in developing mouse lung. We analyzed embryonic day E11.5 lungs, when Nkx2.1 expressing cells are undergoing predominantly proliferation, and day E19.5, when Nkx2.1 expressing cells are undergoing predominantly differentiation. Many highly bound targets are known and well described, such as surfactant proteins and secretoglobins. Unique or common target genes involved in a variety of developmental and tumorigenic pathways were identified at each developmental time point. Positive regulation of cell proliferation was the highest overrepresented biological process at E11.5 while ion transport was the highest overrepresented biological process at E19.5. New identified targets include proliferation related genes such as E2F3, Met, Ccnb1, and Ccnb2. Nkx2.1 downregulation in mouse epithelial and human carcinoma cell lines reduced cell proliferation by arresting cells in the G2/M phase. Reduced expression of Nkx2.1 target genes in both cell lines supports a direct role of Nkx2.1 in regulation of cell proliferation genes. The identification of these transcriptional regulatory pathways in vivo aid us to understand Nkx2.1 function in lung development and link it to disease, since many of the identified targets are aberrantly up regulated in cancer cells. Developing mouse lung, 2 developmental time points E11.5 and E19.5, genomic DNA fragments immunoprecipitated with a-Nkx2.1 (07-601, Upstate-Millipore) vs input, E11.5, 2 biological replicates and E19.5, 3 biological replicates

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Gene expression in Mob1DKO mouse lung

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