Expression Profiles of the Mouse Lung Identify a Molecular Signature of Time-to-Birth (original) (raw)
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The molecular basis of lung morphogenesis
Mechanisms of Development, 2000
To form a diffusible interface large enough to conduct respiratory gas exchange with the circulation, the lung endoderm undergoes extensive branching morphogenesis and alveolization, coupled with angiogenesis and vasculogenesis. It is becoming clear that many of the key factors determining the process of branching morphogenesis, particularly of the respiratory organs, are highly conserved through evolution. Synthesis of information from null mutations in Drosophila and mouse indicates that members of the sonic hedgehog/patched/ smoothened/Gli/FGF/FGFR/sprouty pathway are functionally conserved and extremely important in determining respiratory organogenesis through mesenchymal±epithelial inductive signaling, which induces epithelial proliferation, chemotaxis and organ-speci®c gene expression. Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc ®nger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Signaling by the IGF, EGF and TGF-b/BMP pathways, extracellular matrix components and integrin signaling pathways also directs lung morphogenesis as well as proximo-distal lung epithelial cell lineage differentiation. Soluble factors secreted by lung mesenchyme comprise a`compleat' inducer of lung morphogenesis. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as FGFR, EGFR, IGFR, PDGFR and c-met stimulate lung morphogenesis. On the other hand, cognate receptors with serine/threonine kinase intracellular signaling domains, such as the TGF-b receptor family are inhibitory, although BMP4 and BMPR also play key inductive roles. Pulmonary neuroendocrine cells differentiate earliest in gestation from among multipotential lung epithelial cells. MASH1 null mutant mice do not develop PNE cells. Proximal and distal airway epithelial phenotypes differentiate under distinct transcriptional control mechanisms. It is becoming clear that angiogenesis and vasculogenesis of the pulmonary circulation and capillary network are closely linked with and may be necessary for lung epithelial morphogenesis. Like epithelial morphogenesis, pulmonary vascularization is subject to a ®ne balance between positive and negative factors. Angiogenic and vasculogenic factors include VEGF, which signals through cognate receptors¯k and¯t, while novel anti-angiogenic factors include EMAP II. q
Molecular Mechanisms of Early Lung Specification and Branching Morphogenesis
Pediatric Research, 2005
The "hard wiring" encoded within the genome that determines the emergence of the laryngotracheal groove and subsequently early lung branching morphogenesis is mediated by finely regulated, interactive growth factor signaling mechanisms that determine the automaticity of branching, interbranch length, stereotypy of branching, left-right asymmetry, and finally gas diffusion surface area. The extracellular matrix is an important regulator as well as a target for growth factor signaling in lung branching morphogenesis and alveolarization. Coordination not only of epithelial but also endothelial branching morphogenesis determines bronchial branching and the eventual alveolar-capillary interface. Improved prospects for lung protection, repair, regeneration, and engineering will depend on more detailed understanding of these processes. Herein, we concisely review the functionally integrated morphogenetic signaling network comprising the critical bone morphogenetic protein, fibroblast growth factor, Sonic hedgehog, transforming growth factor-, vascular endothelial growth factor, and Wnt signaling pathways that specify and drive early embryonic lung morphogenesis. (Pediatr Res 57: 1-12, 2005) Abbreviations BMP, bone morphogenetic protein DKK, Dickkopf EGF (R), epidermal growth factor (receptor) ERK, extracellular regulated kinase FGF (R), fibroblast growth factor (receptor) FN, fibronectin LRP, lipoprotein receptor-related proteins MAP, membrane-associated protein PDGF, platelet-derived growth factor RAR, retinoic acid receptor sFRP, secreted Frizzled-related protein SHH, Sonic hedgehog Sp-C, surfactant protein C TGF-␣ (), transforming growth factor alpha (beta) VEGF (R), vascular endothelial growth factor (receptor)
Frontiers in Zoology, 2012
Gas exchangers fundamentally form by branching morphogenesis (BM), a mechanistically profoundly complex process which derives from coherent expression and regulation of multiple genes that direct cell-to-cell interactions, differentiation, and movements by signaling of various molecular morphogenetic cues at specific times and particular places in the developing organ. Coordinated expression of growth-instructing factors determines sizes and sites where bifurcation occurs, by how much a part elongates before it divides, and the angle at which branching occurs. BM is essentially induced by dualities of factors where through feedback-or feed forward loops agonists/antagonists are activated or repressed. The intricate transactions between the development orchestrating molecular factors determine the ultimate phenotype. From the primeval time when the transformation of unicellular organisms to multicellular ones occurred by systematic accretion of cells, BM has been perpetually conserved. Canonical signalling, transcriptional pathways, and other instructive molecular factors are commonly employed within and across species, tissues, and stages of development. While much still remain to be elucidated and some of what has been reported corroborated and reconciled with rest of existing data, notable progress has in recent times been made in understanding the mechanism of BM. By identifying and characterizing the morphogenetic drivers, and markers and their regulatory dynamics, the elemental underpinnings of BM have been more precisely explained. Broadening these insights will allow more effective diagnostic and therapeutic interventions of developmental abnormalities and pathologies in pre-and postnatal lungs. Conservation of the molecular factors which are involved in the development of the lung (and other branched organs) is a classic example of nature's astuteness in economically utilizing finite resources. Once purposefully formed, well-tested and tried ways and means are adopted, preserved, and widely used to engineer the most optimal phenotypes. The material and time costs of developing utterly new instruments and routines with every drastic biological change (e.g. adaptation and speciation) are circumvented. This should assure the best possible structures and therefore functions, ensuring survival and evolutionary success.
Molecular determinants of lung development
Annals of the American Thoracic Society, 2013
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and en...
Genetic Control of Lung Development
Biology of the Neonate, 2003
Lung organogenesis is a developmental process that starts in human 4-5 weeks after conception and continues during the first years of life. It can be subdivided in six different stages: embryonic, pseudoglandular, canalicular, saccular and alveolar stage and stage of vascular maturation. In each of these periods, multiple molecules like transcription factors, growth factors and other signaling molecules and their respective receptors control and coordinate the course of events by a distinct expression and activity over space and time. Epithelial-mesenchymal interactions, physiological mechanical forces as well as humoral factors modulate some of these expression patterns. Although numerous key players and their mode of action have been discovered, many wait to be unveiled. Herein, we will summarize the current concepts of lung development with special consideration of the genetic control of lung genesis, growth and maturation.
Iroquois genes influence proximo-distal morphogenesis during rat lung development
AJP: Lung Cellular and Molecular Physiology, 2006
Iroquois genes influence proximo-distal morphogenesis during rat lung development. Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in -tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh-and Gli 2-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.
The branching programme of mouse lung development
Nature, 2008
Mammalian lungs are branched networks containing thousands to millions of airways arrayed in intricate patterns that are crucial for respiration. How such trees are generated during development, and how the developmental patterning information is encoded, have long fascinated biologists and mathematicians. However, models have been limited by a lack of information on the normal sequence and pattern of branching events. Here we present the complete three-dimensional branching pattern and lineage of the mouse bronchial tree, reconstructed from an analysis of hundreds of developmental intermediates. The branching process is remarkably stereotyped and elegant: the tree is generated by three geometrically simple local modes of branching used in three different orders throughout the lung. We propose that each mode of branching is controlled by a genetically encoded subroutine, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine. We show that this hierarchical and modular programme is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs.
Mechanisms of Development, 2008
Tracheal occlusion during lung development accelerates growth in response to increased intraluminal pressure. In order to investigate the role of internal pressure on murine early lung development, we cauterized the tip of the trachea, to occlude it, and thus to increase internal pressure. This method allowed us to evaluate the effect of tracheal occlusion on the first few branch generations and on gene expression. We observed that the elevation of internal pressure induced more than a doubling in branching, associated with increased proliferation, while branch elongation speed increased 3fold. Analysis by RT-PCR showed that Fgf10, Vegf, Sprouty2 and Shh mRNA expressions were affected by the change of intraluminal pressure after 48h of culture, suggesting mechanotransduction via internal pressure of these key developmental genes. Tracheal occlusion did not increase the number of branches of Fgfr2b −/− mice lungs nor of wild type lungs cultured with Fgfr2b antisense RNA. Tracheal occlusion of Fgf10 LacZ/hypomorphic lungs led to the formation of fewer branches than in wild type. We conclude that internal pressure regulates the FGF10-FGFR2b-Sprouty2 pathway and thus the speed of the branching process. Therefore pressure levels, fixed both by epithelial secretion and boundary conditions, can control the branching process via FGF10-FGFR2b-Sprouty2.