CDC42 is Required for Structural Patterning of the Lung During Development.
ABSTRACT The formation of highly branched epithelial structures is critical for the development of many essential organs, including lung, liver, pancreas, kidney and mammary glands. Elongation and branching of these structures require precise control of complex morphogenetic processes that are dependent upon coordinate regulation of cell shape, apical-basal polarity, proliferation, migration, and interactions among multiple cell types. Herein, we demonstrate that temporal-spatial regulation of epithelial cell polarity by the small GTPase, CDC42, is essential for branching morphogenesis of the developing lung. Epithelial cell-specific deletion of CDC42 in fetal mice disrupted epithelial cell polarity, the actin cytoskeleton, intercellular contacts, directional trafficking of proteins, proliferation and mitotic spindle orientation, impairing the organization and patterning of the developing respiratory epithelium and adjacent mesenchyme. Transition from a pseudostratified to a simple columnar epithelium was impaired, consistent with coordinate dysregulation of epithelial cell polarity, mitotic spindle orientation, and repositioning of mitotic cells within the epithelium during cell cycle progression. Expression of sonic hedgehog and its receptor, patched-1, was decreased, while fibroblast growth factor 10 expression in the mesenchyme was expanded, resulting in disruption of branching morphogenesis and bronchiolar smooth muscle formation in this model. CDC42 is required for spatial positioning of proliferating epithelial cells, as well as signaling interactions between the epithelium and mesenchyme and is, therefore, essential for formation and maintenance of the respiratory tract during morphogenesis of the fetal lung.
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ABSTRACT: Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branch-ing morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss- and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.Proceedings of the National Academy of Sciences 11/2013; 110(47). DOI:10.1073/pnas.1311847110 · 9.81 Impact Factor
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ABSTRACT: We investigated discriminating features between enhancers separated from their target genes by at least one intermediate gene/exon (named tele-enhancers in this study) and enhancers residing inside the target gene locus. In this study, we used genome-scale enhancer maps and whole-genome gene expression profiles to establish a large panel of heart tele-enhancers. By contrasting tele-enhancers to proximal heart enhancers located in the neighborhood of heart genes, we observed that heart tele-enhancers employ unique regulatory mechanisms based on cardiac transcription factor SRF, TEAD, and NKX-2.5, while proximal heart enhancers rely on GATA4 factors. A functional analysis shows that tele-enhancers preferentially regulate house-keeping genes and play a metabolic role during heart development. In addition, with 1) lower nucleotide divergence, 2) lower single-nucleotide polymorphism (SNP) density, and 3) smaller proportion of low derived-allele-frequency SNPs, tele-enhancers are significantly more conserved than their proximal counterparts. Similar trends have been observed in non-heart tissues and cell types, suggesting that our findings are general characteristics of tele-enhancers.G3-Genes Genomes Genetics 02/2014; 4(4). DOI:10.1534/g3.114.010447 · 2.51 Impact Factor
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ABSTRACT: Oriented cell division is a key regulator of tissue architecture and crucial for morphogenesis and homeostasis. Balanced regulation of proliferation and differentiation is an essential property of tissues not only to drive morphogenesis but also to maintain and restore homeostasis. In many tissues orientation of cell division is coupled to the regulation of differentiation producing daughters with similar (symmetric cell division, SCD) or differential fate (asymmetric cell division, ACD). This allows the organism to generate cell lineage diversity from a small pool of stem and progenitor cells. Division orientation and/or the ratio of ACD/SCD need to be tightly controlled as loss or an altered division orientation can promote overgrowth, alter tissue architecture and aberrant differentiation, and has been linked to morphogenetic diseases, cancer and aging. A key requirement for oriented division is the presence of a polarity axis, which can be established through cell intrinsic and/or extrinsic signals. Polarity proteins translate such internal and external cues to drive polarization. In this review we will focus on the role of the polarity complex aPKC/Par3/Par6 in the regulation of division orientation and cell fate in different mammalian epithelia. We will compare the conserved function of this complex in mitotic spindle orientation and distribution of cell fate determinants and highlight common and differential mechanisms in which this complex is used by tissues to adapt division orientation and cell fate to the specific properties of the epithelium.Experimental Cell Research 08/2014; 328(2). DOI:10.1016/j.yexcr.2014.08.008 · 3.37 Impact Factor