Molecular Mechanisms of Lung Development and Lung Branching Morphogenesis

2017 ◽  
pp. 658-666.e4 ◽  
Author(s):  
Sharareh Shojaie ◽  
Martin Post
Keyword(s):  
Lung Development ◽  
Molecular Mechanisms ◽  
Branching Morphogenesis ◽  
Lung Branching

Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins

2004 ◽  
Vol 286 (2) ◽  
pp. L293-L300 ◽  
Author(s):  
Wei Shi ◽  
Hui Chen ◽  
Jianping Sun ◽  
Cheng Chen ◽  
Jingsong Zhao ◽  
...  
Keyword(s):  
Lung Development ◽  
Molecular Mechanisms ◽  
Branching Morphogenesis ◽  
Airway Epithelial Cells ◽  
Clara Cell ◽  
Cell Protein ◽  
Mouse Lung ◽  
Mrna Levels ◽  
Embryonic Lung ◽  
Lung Branching

Early embryonic lung branching morphogenesis is regulated by many growth factor-mediated pathways. Bone morphogenetic protein 4 (BMP4) is one of the morphogens that stimulate epithelial branching in mouse embryonic lung explant culture. To further understand the molecular mechanisms of BMP4-regulated lung development, we studied the biological role of Smad-ubiquitin regulatory factor 1 (Smurf1), an ubiquitin ligase specific for BMP receptor-regulated Smads, during mouse lung development. The temporo-spatial expression pattern of Smurf1 in mouse embryonic lung was first determined by quantitative real-time PCR and immunohistochemistry. Overexpression of Smurf1 in airway epithelial cells by intratracheal introduction of recombinant adenoviral vector dramatically inhibited embryonic day (E) 11.5 lung explant growth in vitro. This inhibition of lung epithelial branching was restored by coexpression of Smad1 or by addition of soluble BMP4 ligand into the culture medium. Studies at the cellular level show that overexpression of Smurf1 reduced epithelial cell proliferation and differentiation, as documented by reduced PCNA-positive cell index and by reduced mRNA levels for surfactant protein C and Clara cell protein 10 expression. Further studies found that overexpression of Smurf1 reduced BMP-specific Smad1 and Smad5, but not Smad8, protein levels. Thus overexpression of Smurf1 specifically promotes Smad1 and Smad5 ubiquitination and degradation in embryonic lung epithelium, thereby modulating the effects of BMP4 on embryonic lung growth.

scholarly journals The extracellular matrix gene, Svep1, orchestrates airway patterning and the transition from lung branching morphogenesis to alveolar maturation in the mouse

2021 ◽  
Author(s):  
Nicole Foxworth ◽  
Julie Wells ◽  
Sara Ocaña-Lopez ◽  
Sandrine Muller ◽  
James Denegre ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lung Development ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Branching Morphogenesis ◽  
Extracellular Matrix Protein ◽  
Lung Hypoplasia ◽  
Matrix Gene ◽  
Lung Branching

Proper lung development and function requires two independent but interrelated processes: branching morphogenesis to form the airway tree, and alveolar cell differentiation for peripheral gas exchange. The disruption of either branching or differentiation results in severe respiratory deficiencies and often in neonatal death. The molecular mechanisms that control branching patterns and the transition to alveolar differentiation are not completely understood. Here we report on the in vitro and in vivo characterization of the lungs of mouse embryos lacking a functional Svep1 gene. Our data demonstrate that the SVEP1 extracellular matrix protein is critical for the process of transitioning from branching to alveolar maturation. Svep1-/- embryos on a C57BL/6J genetic background are characterized by hypoplastic lungs and a disorganized increase in distal airway tips which disrupts airway architecture and lobe shape. The lungs of Svep1 knockout embryos also have defects in alveolar differentiation. In vitro lung explant experiments demonstrated that SVEP1 normally inhibits branching morphogenesis and that treatment with a SVEP1 peptide can rescue the branching defects observed in Svep1 knockouts. Our findings reveal for the first time that Svep1 is essential for constructing the basic airway architecture and for the transition from lung branching to alveolar differentiation. Our results suggest therapeutic strategies to enhance lung development in patients with life-threatening respiratory disorders such as the lung hypoplasia and prematurity observed in neonates with congenital diaphragmatic hernia (CDH).

Potential role of RGD-binding integrins in mammalian lung branching morphogenesis

Development ◽  
1991 ◽  
Vol 112 (2) ◽  
pp. 551-558 ◽  
Author(s):  
J. Roman ◽  
C.W. Little ◽  
J.A. McDonald
Keyword(s):  
Lung Development ◽  
Branching Morphogenesis ◽  
Integrin Receptors ◽  
Murine Lung ◽  
Cell Matrix ◽  
Matrix Interactions ◽  
Mammalian Lung ◽  
Cell Matrix Interactions ◽  
Lung Branching

Cell-matrix interactions are generally considered critical for normal lung development. This is particularly likely to be true during the glandular stage, when the primitive airways are formed through a process termed branching morphogenesis. Integrins, transmembrane receptors that bind to extracellular matrices, are likely to mediate important interactions between embryonic cells and their matrices during branching morphogenesis. In this report, we examine the role of integrin receptors in this process. Immunohistochemical studies revealed that the integrins VLA 3, VLA 5 and integrin receptors to vitronectin are expressed in the epithelium and/or mesenchyme during the glandular stage of murine lung development. To correlate expression with function, an in vitro model of murine lung branching morphogenesis was utilized to examine branching in the presence of inhibitors of ligand binding to integrin receptors. One such reagent, a hexapeptide containing the RGD (Arg-Gly-Asp) sequence, diminished branching and resulted in an abnormal morphology, whereas a control peptide RGESP (Arg-Gly-Glu-Ser-Pro) had no effect. These findings suggest a critical role for cell-matrix interactions mediated via integrin receptors in early stages of mammalian lung development.

scholarly journals Human lung branching morphogenesis is orchestrated by the spatiotemporal distribution of ACTA2, SOX2, and SOX9

2018 ◽  
Vol 314 (1) ◽  
pp. L144-L149 ◽  
Author(s):  
Soula Danopoulos ◽  
Irving Alonso ◽  
Matthew E. Thornton ◽  
Brendan H. Grubbs ◽  
Saverio Bellusci ◽  
...  
Keyword(s):  
Lung Development ◽  
Progenitor Cell ◽  
Human Lung ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Double Positive ◽  
Progenitor Cell Population ◽  
Positive Population ◽  
Pseudoglandular Stage ◽  
Lung Branching

Lung morphogenesis relies on a number of important processes, including proximal-distal patterning, cell proliferation, migration and differentiation, as well as epithelial-mesenchymal interactions. In mouse lung development, SOX2+ cells are localized in the proximal epithelium, whereas SOX9+ cells are present in the distal epithelium. We show that, in human lung, expression of these transcription factors differs, in that during the pseudoglandular stage distal epithelial progenitors at the tips coexpress SOX2 and SOX9. This double-positive population was no longer present by the canalicular stages of development. As in mouse, the human proximal epithelial progenitors express solely SOX2 and are surrounded by smooth muscle cells (SMCs) both in the proximal airways and at the epithelial clefts. Upon Ras-related C3 botulinum toxin substrate 1 inhibition, we noted decreased branching, as well as increased SMC differentiation, attenuated peristalsis, and a reduction in the distal double-positive SOX2/SOX9 progenitor cell population. Thus, the presence of SOX2/SOX9 double-positive progenitor cells in the distal epithelium during the pseudoglandular stage of human lung development appears to be critical to proximal-distal patterning and lung branching. Moreover, SMCs promote a SOX2 proximal phenotype and seem to suppress the SOX9+ population.

scholarly journals Lung branching morphogenesis is accompanied by temporal metabolic changes towards a glycolytic preference

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hugo Fernandes-Silva ◽  
Marco G. Alves ◽  
Henrique Araújo-Silva ◽  
Ana M. Silva ◽  
Jorge Correia-Pinto ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Glucose Consumption ◽  
Branching Morphogenesis ◽  
Explant Culture ◽  
Metabolic Changes ◽  
Specific Expression ◽  
Expression Levels ◽  
Early Stages ◽  
Lung Branching

Abstract Background Lung branching morphogenesis is characterized by epithelial-mesenchymal interactions that ultimately define the airway conducting system. Throughout this process, energy and structural macromolecules are necessary to sustain the high proliferative rates. The extensive knowledge of the molecular mechanisms underlying pulmonary development contrasts with the lack of data regarding the embryonic lung metabolic requirements. Here, we studied the metabolic profile associated with the early stages of chicken pulmonary branching. Methods In this study, we used an ex vivo lung explant culture system and analyzed the consumption/production of extracellular metabolic intermediates associated with glucose catabolism (alanine, lactate, and acetate) by 1H-NMR spectroscopy in the culture medium. Then, we characterized the transcript levels of metabolite membrane transporters (glut1, glut3, glut8, mct1, mct3, mct4, and mct8) and glycolytic enzymes (hk1, hk2, pfk1, ldha, ldhb, pdha, and pdhb) by qPCR. ldha and ldhb mRNA spatial localization was determined by in situ hybridization. Proliferation was analyzed by directly assessing DNA synthesis using an EdU-based assay. Additionally, we performed western blot to analyze LDHA and LDHT protein levels. Finally, we used a Clark-Type Electrode to assess the lung explant's respiratory capacity. Results Glucose consumption decreases, whereas alanine, lactate, and acetate production progressively increase as branching morphogenesis proceeds. mRNA analysis revealed variations in the expression levels of key enzymes and transporters from the glycolytic pathway. ldha and ldhb displayed a compartment-specific expression pattern that resembles proximal–distal markers. In addition, high proliferation levels were detected at active branching sites. LDH protein expression levels suggest that LDHB may account for the progressive rise in lactate. Concurrently, there is a stable oxygen consumption rate throughout branching morphogenesis. Conclusions This report describes the temporal metabolic changes that accompany the early stages of chicken lung branching morphogenesis. Overall, the embryonic chicken lung seems to shift to a glycolytic lactate-based metabolism as pulmonary branching occurs. Moreover, this metabolic rewiring might play a crucial role during lung development.

Cellular and molecular mechanisms involved in branching morphogenesis of the Drosophila tracheal system

2004 ◽  
Vol 97 (6) ◽  
pp. 2347-2353 ◽  
Author(s):  
Clemens Cabernard ◽  
Marc Neumann ◽  
Markus Affolter
Keyword(s):  
Lung Development ◽  
Recent Progress ◽  
Molecular Mechanisms ◽  
Genetic Network ◽  
Branching Morphogenesis ◽  
Model Systems ◽  
Tracheal System ◽  
Organ Systems ◽  
Invertebrate Model ◽  
Complex Organ

Recent comparative studies have shown that, in many instances, the genetic network underlying the development of distinct organ systems is similar in invertebrate and vertebrate organisms. Genetically well-characterized, simple invertebrate model systems, such as Caenorhabditis elegans and Drosophila melanogaster, can thus provide useful insight for understanding more complex organ systems in vertebrates. Here, we summarize recent progress in the genetic analysis of tracheal development in Drosophila and compare the results to studies aimed at a better understanding of lung development in mouse and man. Clearly, both striking similarities and important differences are apparent, but it might still be too early to conclude whether the former or the latter prevail.

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