Alterations in gene expression in T1α null lung: a model of deficient alveolar sac development

Millien, Guetchyn; Spira, Avrum; Hinds, Anne; Wang, Junling; Williams, Mary C.; Ramirez, María I.

doi:10.1186/1471-213x-6-35

Cited by 33 publications

(11 citation statements)

References 47 publications

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“…Previous studies on lung maturation focused primarily on genes expressed in lung epithelial cells, such as Klf5 (Wan et al, 2008), Tgfb1 (Zhou et al, 1996), Cebpa (Berg et al, 2006; Martis et al, 2006), Vegf (Zeng et al, 1998), T1a (Millien et al, 2006), GR (Manwani et al, 2009), Carm1 (O’Brien et al, 2010), Pparγ (Simon et al, 2006), Alk5 (Xing et al, 2010) and Pdgfa (Li and Hoyle, 2001). There is far less data on how gene expression in mesenchyme regulates lung maturation.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation

Hsu

Osinski

Campbell

et al. 2011

Developmental Biology

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The Nuclear factor I (NFI) transcription factor family consists of four genes (Nfia, Nfib, Nfic and Nfix) that regulate the development of multiple organ systems in mice and humans. Nfib is expressed in both lung mesenchyme and epithelium and mice lacking Nfib have severe lung maturation defects and die at birth. Here we continue our analysis of the phenotype of Nfib−/− lungs and show that Nfib specifically in lung mesenchyme controls late epithelial and mesenchymal cell proliferation and differentiation. There are more PCNA, BrdU, PHH3 and Ki67 positive cells in Nfib−/− lungs than in wild type lungs at E18.5 and this increase in proliferation marker expression is seen in both epithelial and mesenchymal cells. The loss of Nfib in all lung cells decreases the expression of markers for alveolar epithelial cells (Aqp5 & Sftpc), Clara cells (Scgb1a1) and ciliated cells (Foxj1) in E18.5 lungs. To test for a specific role of Nfib in lung mesenchyme we generated and analyzed Nfibflox/flox, Dermo1-Cre mice. Loss of Nfib only in mesenchyme results in decreased Aqp5, Sftpc and Foxj1 expression, increased cell proliferation, and a defect in sacculation similar to that seen in Nfib−/− mice. In contrast, mesenchyme specific loss of Nfib had no effect on the expression of Scgb1a1 in the airway. Microarray and QPCR analyses indicate that the loss of Nfib in lung mesenchyme affects the expression of genes associated with extracellular matrix, cell adhesion and FGF signaling which could affect distal lung maturation. Our data indicate that mesenchymal Nfib regulates both mesenchymal and epithelial cell proliferation through multiple pathways and that mesenchymal NFI-B-mediated signals are essential for the maturation of distal lung epithelium.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation

Hsu

Osinski

Campbell

et al. 2011

Developmental Biology

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“…Total RNA was harvested from snap frozen tissue samples (n = 3 for each time point), processed, and hybridized to Affymetrix MGU74Av2 arrays [14], [15]. Microarray data were analyzed using Affymetrix Microarray Suite 5.0 software (MAS5.0), and target intensity for each chip was set to 100 for normalization.…”

Section: Methodsmentioning

confidence: 99%

Transcription Factor Klf4, Induced in the Lung by Oxygen at Birth, Regulates Perinatal Fibroblast and Myofibroblast Differentiation

et al. 2013

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The fluid-filled lung exists in relative hypoxia in utero (∼25 mm Hg), but at birth fills with ambient air where the partial pressure of oxygen is ∼150 mm Hg. The impact of this change was studied in mouse lung with microarrays to analyze gene expression one day before, and 2, 6, 12 and 24 hours after birth into room air or 10% O2. The expression levels of >150 genes, representing transcriptional regulation, structure, apoptosis and antioxidants were altered 2 hrs after birth in room air but blunted or absent with birth in 10% O2. Kruppel-like factor 4 (Klf4), a regulator of cell growth arrest and differentiation, was the most significantly altered lung gene at birth. Its protein product was expressed in fibroblasts and airway epithelial cells. Klf4 mRNA was induced in lung fibroblasts exposed to hyperoxia and constitutive expression of Klf4 mRNA in Klf4-null fibroblasts induced mRNAs for p21cip1/Waf1, smooth muscle actin, type 1 collagen, fibronectin and tenascin C. In Klf4 perinatal null lung, p21cip1/Waf1mRNA expression was deficient prior to birth and associated with ongoing cell proliferation after birth; connective tissue gene expression was deficient around birth and smooth muscle actin protein expression was absent from myofibroblasts at tips of developing alveoli; p53, p21cip1/Waf1 and caspase-3 protein expression were widespread at birth suggesting excess apoptosis compared to normal lung. We propose that the changing oxygen environment at birth acts as a physiologic signal to induce lung Klf4 mRNA expression, which then regulates proliferation and apoptosis in fibroblasts and airway epithelial cells, and connective tissue gene expression and myofibroblast differentiation at the tips of developing alveoli.

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“…These mice show narrower airspaces and die because they are unable to inflate their lungs at birth [43]. While the molecular mechanism behind this phenotype is unknown, altered alveolar differentiation appears to correlate with abnormal expression of some genes, such as ephrinA3 and p21Cip1 [44].…”

Section: Podoplanin In Embryonic Development and Differentiationmentioning

confidence: 99%

Podoplanin in Inflammation and Cancer

Quintanilla

Montero-Montero

Renart

et al. 2019

IJMS

167

182

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Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.

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Alterations in gene expression in T1α null lung: a model of deficient alveolar sac development

Cited by 33 publications

References 47 publications

Mesenchymal Nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation

Mesenchymal Nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation

Transcription Factor Klf4, Induced in the Lung by Oxygen at Birth, Regulates Perinatal Fibroblast and Myofibroblast Differentiation

Podoplanin in Inflammation and Cancer

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