Genetic Testing for Neonatal Respiratory Disease

Genetic mechanisms are now recognized as rare causes of neonatal lung disease. Genes potentially responsible for neonatal lung disease include those encoding proteins important in surfactant function and metabolism, transcription factors important in lung development, proteins involved in ciliary assembly and function, and various other structural and immune regulation genes. The phenotypes of infants with genetic causes of neonatal lung disease may have some features that are difficult to distinguish clinically from more common, reversible causes of lung disease, and from each other. Multigene panels are now available that can allow for a specific diagnosis, providing important information for treatment and prognosis. This review discusses genes in which abnormalities are known to cause neonatal lung disease and their associated phenotypes, and advantages and limitations of genetic testing.

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The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.767454 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mu-Hang Li ◽

Leilani M. Marty-Santos ◽

Paul R. van Ginkel ◽

Aubrey E. McDermott ◽

Andrew J. Rasky ◽

...

Keyword(s):

Transcription Factors ◽

Lung Development ◽

Lung Fibroblasts ◽

Loss Of Function ◽

Specific Loss ◽

Skeletal Patterning ◽

The Matrix ◽

Distal Lung ◽

And Function ◽

Matrix Metalloproteinase 12

Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5afafbbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.

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Impact of prematurity on rabbit lung development: a key factor for mimicking chronic neonatal lung disease

10.1183/13993003.congress-2021.oa1220 ◽

2021 ◽

Author(s):

Matteo Storti ◽

Francesca Ricci ◽

Costanza Casiraghi ◽

Chiara Catozzi ◽

Francesca Ravanetti ◽

...

Keyword(s):

Lung Disease ◽

Lung Development ◽

Rabbit Lung ◽

Key Factor ◽

Neonatal Lung ◽

Chronic Neonatal Lung Disease

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POPDC proteins and cardiac function

Biochemical Society Transactions ◽

10.1042/bst20190249 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1393-1404 ◽

Cited By ~ 4

Author(s):

Thomas Brand

Keyword(s):

Potential Role ◽

Striated Muscle ◽

Short Review ◽

Effector Proteins ◽

Muscle Disease ◽

Disease Genes ◽

Protein Protein Interaction ◽

Interaction Partners ◽

And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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Faculty Opinions recommendation of Palmitoylation of TEAD transcription factors is required for their stability and function in hippo pathway signaling.

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

10.3410/f.726054023.793516113 ◽

2016 ◽

Author(s):

Mariann Bienz

Keyword(s):

Transcription Factors ◽

Hippo Pathway ◽

And Function

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NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22115902 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5902

Author(s):

Stefan Nagel ◽

Claudia Pommerenke ◽

Corinna Meyer ◽

Hans G. Drexler

Keyword(s):

Dendritic Cells ◽

Transcription Factors ◽

Cell Lines ◽

Expression Profiling ◽

Regulatory Network ◽

Homeobox Gene ◽

Leukemia Cell Line ◽

Specific Gene ◽

Rna Seq ◽

And Function

Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.

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Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽

10.1177/17590914211009730 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110097

Author(s):

Kui Cui ◽

Fan Yang ◽

Turan Tufan ◽

Muhammad U. Raza ◽

Yanqiang Zhan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcription Factors ◽

Disease Model ◽

Neuronal Loss ◽

Mrna Levels ◽

Gene Therapies ◽

Protein Levels ◽

Dopaminergic Systems ◽

And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

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Predictors of home oxygen duration in chronic neonatal lung disease

Pediatric Pulmonology ◽

10.1002/ppul.25257 ◽

2021 ◽

Vol 56 (5) ◽

pp. 992-999

Author(s):

Matthew D. Wong ◽

Melissa Neylan ◽

Gordon Williams ◽

Syeda F. Zahir ◽

Jasneek Chawla

Keyword(s):

Lung Disease ◽

Neonatal Lung ◽

Chronic Neonatal Lung Disease

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Transcription Factors in the Development and Function of Group 2 Innate Lymphoid Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20061377 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1377 ◽

Cited By ~ 6

Author(s):

Takashi Ebihara ◽

Ichiro Taniuchi

Keyword(s):

Transcription Factors ◽

Physiological State ◽

Allergic Inflammation ◽

Allergic Diseases ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Th2 Cytokine ◽

Parasitic Worm ◽

Group 2 ◽

And Function

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells and are a major source of innate TH2 cytokine secretion upon allergen exposure or parasitic-worm infection. Accumulating studies have revealed that transcription factors, including GATA-3, Bcl11b, Gfi1, RORα, and Ets-1, play a role in ILC2 differentiation. Recent reports have further revealed that the characteristics and functions of ILC2 are influenced by the physiological state of the tissues. Specifically, the type of inflammation strongly affects the ILC2 phenotype in tissues. Inhibitory ILC2s, memory-like ILC2s, and ex-ILC2s with ILC1 features acquire their characteristic properties following exposure to their specific inflammatory environment. We have recently reported a new ILC2 population, designated as exhausted-like ILC2s, which emerges after a severe allergic inflammation. Exhausted-like ILC2s are featured with low reactivity and high expression of inhibitory receptors. Therefore, for a more comprehensive understanding of ILC2 function and differentiation, we review the recent knowledge of transcriptional regulation of ILC2 differentiation and discuss the roles of the Runx transcription factor in controlling the emergence of exhausted-like ILC2s. The concept of exhausted-like ILC2s sheds a light on a new aspect of ILC2 biology in allergic diseases.

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