Developmental Pathways Underlying Lung Development and Congenital Lung Disorders

Lung organogenesis is a highly coordinated process governed by a network of conserved signaling pathways that ultimately control patterning, growth, and differentiation. This rigorously regulated developmental process culminates with the formation of a fully functional organ. Conversely, failure to correctly regulate this intricate series of events results in severe abnormalities that may compromise postnatal survival or affect/disrupt lung function through early life and adulthood. Conditions like congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchogenic cysts, and congenital diaphragmatic hernia display unique forms of lung abnormalities. The etiology of these disorders is not yet completely understood; however, specific developmental pathways have already been reported as deregulated. In this sense, this review focuses on the molecular mechanisms that contribute to normal/abnormal lung growth and development and their impact on postnatal survival.

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Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus

Human Genetics ◽

10.1007/s00439-021-02344-6 ◽

2021 ◽

Author(s):

Uirá Souto Melo ◽

Juliette Piard ◽

Björn Fischer-Zirnsak ◽

Marius-Konstantin Klever ◽

Robert Schöpflin ◽

...

Keyword(s):

Lung Development ◽

Molecular Mechanisms ◽

Developmental Process ◽

Regulatory Elements ◽

Normal Lung ◽

Ultrasound Screening ◽

Topologically Associating Domains ◽

Complex Genomic Rearrangement ◽

Isolated Lung ◽

Lung Agenesis

AbstractDuring human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease.

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Making a mark: the role of RNA modifications in plant biology

The Biochemist ◽

10.1042/bio20200046 ◽

2020 ◽

Vol 42 (4) ◽

pp. 26-30

Author(s):

Matthew T. Parker ◽

Katarzyna Knop ◽

Gordon G. Simpson

Keyword(s):

Messenger Rna ◽

Growth And Development ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Biological Significance ◽

Plant Biology ◽

Developmental Pathways ◽

Rna Modifications ◽

Feature Article

Plants coordinate their growth and development through complex regulatory networks involving changes in the expression of thousands of genes. Many developmental pathways are regulated at the level of messenger RNA (mRNA) through alternative choices in mRNA processing. These choices can have consequences for the localization, stability or translatability of mRNAs. One of the key ways in which RNAs are processed is by the methylation of the RNA base adenosine – a modification known as m6A. Even though it was first discovered in the 1970s, the biological significance of m6A marks has only recently become clear. In this feature article, we identify the factors controlling the writing and reading of m6A modifications in plants. We also highlight some of the features of plant development that depend on m6A and explore the recently discovered molecular mechanisms that use m6A to control development or response to environmental stress.

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Faculty Opinions recommendation of FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1032815.374906 ◽

2006 ◽

Author(s):

Simon Hayward

Keyword(s):

Growth And Development ◽

Lung Growth ◽

Shh Signaling

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Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Science Advances ◽

10.1126/sciadv.abd7974 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabd7974

Author(s):

Michela Serresi ◽

Sonia Kertalli ◽

Lifei Li ◽

Matthias Jürgen Schmitt ◽

Yuliia Dramaretska ◽

...

Keyword(s):

Cancer Cells ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Developmental Process ◽

Epithelial Mesenchymal Transition ◽

Chromatin Remodelers ◽

Mesenchymal Transition ◽

Signature Genes ◽

Chromatin Regulators ◽

The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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Molecular Responses during Plant Grafting and Its Regulation by Auxins, Cytokinins, and Gibberellins

Biomolecules ◽

10.3390/biom9090397 ◽

2019 ◽

Vol 9 (9) ◽

pp. 397 ◽

Cited By ~ 4

Author(s):

Anket Sharma ◽

Bingsong Zheng

Keyword(s):

Plant Hormones ◽

Growth And Development ◽

Molecular Mechanisms ◽

Main Process ◽

Graft Union ◽

Physiological Processes ◽

Current Review ◽

Postharvest Life ◽

Successful Production

Plant grafting is an important horticulture technique used to produce a new plant after joining rootstock and scion. This is one of the most used techniques by horticulturists to enhance the quality and production of various crops. Grafting helps in improving the health of plants, their yield, and the quality of plant products, along with the enhancement of their postharvest life. The main process responsible for successful production of grafted plants is the connection of vascular tissues. This step determines the success rate of grafts and hence needs to be studied in detail. There are many factors that regulate the connection of scion and stock, and plant hormones are of special interest for researchers in the recent times. These phytohormones act as signaling molecules and have the capability of translocation across the graft union. Plant hormones, mainly auxins, cytokinins, and gibberellins, play a major role in the regulation of various key physiological processes occurring at the grafting site. In the current review, we discuss the molecular mechanisms of graft development and the phytohormone-mediated regulation of the growth and development of graft union.

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Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections

Frontiers in Medicine ◽

10.3389/fmed.2015.00055 ◽

2015 ◽

Vol 2 ◽

Cited By ~ 7

Author(s):

William Domm ◽

Ravi S. Misra ◽

Michael A. Oâ€™Reilly

Keyword(s):

Lung Development ◽

Early Life ◽

Viral Infections ◽

Oxygen Exposure ◽

Respiratory Viral Infections

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Expression of epidermal growth factor and surfactant proteins during postnatal and compensatory lung growth

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00053.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. L981-L990 ◽

Cited By ~ 32

Author(s):

David J. Foster ◽

Xiao Yan ◽

Dennis J. Bellotto ◽

Orson W. Moe ◽

Herbert K. Hagler ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Lung Development ◽

Surfactant Proteins ◽

Nuclear Antigen ◽

Lung Growth ◽

Alveolar Cell ◽

Epidermal Growth ◽

Postnatal Lung Development ◽

Proliferating Cell

We examined whether lung growth after pneumonectomy (PNX) invokes normal signaling pathways of postnatal development. We qualitatively and quantitatively assessed the immunoexpression of epidermal growth factor (EGF), its receptor (EGFR), surfactant proteins (SP) [SP-A and -D and surfactant proproteins (proSP)-B and -C] and proliferating cell nuclear antigen (PCNA) in immature and mature dog lung. We also assayed these proteins in lungs of immature dogs 3 wk or 10 mo after they underwent right PNX compared with simultaneous matched sham controls. During maturation, alveolar cell proliferation is regionally regulated in parallel with EGF and EGFR levels and inversely correlated with SP-A and proSP-C levels. In contrast, post-PNX lung growth is not associated with EGF or EGFR upregulation but with markedly increased SP-A level and moderately increased SP-D level; proSP-B and proSP-C levels did not change. We conclude that 1) signaling of EGF axis and differential regulation of SPs persist during postnatal lung development, 2) post-PNX lung growth is not a simple recapitulation of maturational responses, and 3) SP-A and SP-D may modulate post-PNX lung growth.

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A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress

Endocrinology ◽

10.1210/en.2008-0633 ◽

2008 ◽

Vol 149 (10) ◽

pp. 4892-4900 ◽

Cited By ~ 255

Author(s):

Courtney J. Rice ◽

Curt A. Sandman ◽

Mohammed R. Lenjavi ◽

Tallie Z. Baram

Keyword(s):

Mouse Model ◽

Paraventricular Nucleus ◽

Life Stress ◽

Early Life ◽

Molecular Mechanisms ◽

Early Life Stress ◽

Plasma Corticosterone ◽

Mrna Levels ◽

Dependent Manner ◽

Basal Plasma

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

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Functions of PPR Proteins in Plant Growth and Development

International Journal of Molecular Sciences ◽

10.3390/ijms222011274 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11274

Author(s):

Xiulan Li ◽

Mengdi Sun ◽

Shijuan Liu ◽

Qian Teng ◽

Shihui Li ◽

...

Keyword(s):

Plant Growth ◽

Stress Responses ◽

Rna Processing ◽

Growth And Development ◽

Molecular Mechanisms ◽

Rna Binding ◽

Plant Mitochondria ◽

Research Progress ◽

Plant Growth And Development ◽

Ppr Proteins

Pentatricopeptide repeat (PPR) proteins form a large protein family in land plants, with hundreds of different members in angiosperms. In the last decade, a number of studies have shown that PPR proteins are sequence-specific RNA-binding proteins involved in multiple aspects of plant organellar RNA processing, and perform numerous functions in plants throughout their life cycle. Recently, computational and structural studies have provided new insights into the working mechanisms of PPR proteins in RNA recognition and cytidine deamination. In this review, we summarized the research progress on the functions of PPR proteins in plant growth and development, with a particular focus on their effects on cytoplasmic male sterility, stress responses, and seed development. We also documented the molecular mechanisms of PPR proteins in mediating RNA processing in plant mitochondria and chloroplasts.

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