Unique spatial and cellular expression patterns of Hoxa5, Hoxb4, and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia

Volpe, MaryAnn V.; Wang, Karen Ting Wai; Nielsen, Heber C.; Chinoy, Mala R.

doi:10.1002/bdra.20481

Cited by 21 publications

(27 citation statements)

References 73 publications

(159 reference statements)

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“…Consistent with other studies in mouse and human lung, our results show that ␣ 2 -integrin is expressed in epithelia and adjacent mesenchyme of branching airway tips, whereas ␣ 3 -integrin is expressed in established airway branches (15,34,62). ␣ 2 ␤ 1 -integrin receptors are thought to promote mesenchymal-epithelial cell contacts as epithelial cells migrate into surrounding mesenchyme and associate with extracellular matrix binding partners and other cells (16,67).…”

Section: Discussionsupporting

confidence: 91%

“…A direct interaction between HoxB5 and E-cadherin is also less likely as E-cadherin is exclusively localized to epithelial cells (24,25). However, we and others have shown that certain Hox genes and divergent homeobox genes are localized to lung epithelial cells (22,32,42,43,61,62). We have not yet investigated the expression pattern of other Hox genes in BPS and CCAM, but it is possible that other Hox genes are aberrantly expressed in these lung lesions either independently of HoxB5 or through Hox gene auto-and cross-regulation, that might contribute to more direct Hox regulation of epithelial-expressed cell adhesion molecules in BPS and CCAM (6, 26, 44, 60, 68).…”

Section: Discussionmentioning

confidence: 92%

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Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

Volpe

Chung²,

Ulm³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Volpe MV, Chung E, Ulm JP, Gilchrist BF, Ralston S, Wang KT, Nielsen HC. Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation. Am J Physiol Lung Cell Mol Physiol 297: L143-L152, 2009. First published May 1, 2009 doi:10.1152/ajplung.90618.2008.-In many organs, integrins and cadherins are partly regulated by Hox genes, but their interactions in airway morphogenesis and congenital lung diseases are unknown. We previously showed that the Hox protein HoxB5 is abnormally increased in bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM), congenital lung lesions with abnormal airway branching. We now report on ␣ 2-, ␣3-, and ␤1-integrin and E-cadherin expression in normal human lung and in BPS and CCAM tissue previously shown to have abnormal HoxB5 expression and on the relationship of cell adhesion molecule expression to Hoxb5 regulation. ␣ 2-, ␣3-, and ␤ 1 -integrins and E-cadherin expression in normal human lung and BPS and CCAM were evaluated using Western blot and immunohistochemistry. Fetal mouse lung fibroblasts with Hoxb5-specific siRNA downregulation were evaluated for ␣ 2-integrin protein levels by Western blot. Compared with normal human lung, a previously undetected ␣ 2-integrin isoform potentially lacking essential cytoplasmic sequences was significantly increased in BPS and CCAM, and ␣ 2-integrin spatial and cellular expression was more intense. Ecadherin protein levels were also significantly increased, whereas ␣ 3 increased in CCAM compared with canalicular, but not with alveolar, stage lung. ␤ 1-integrin levels were unchanged. We conclude that in BPS and CCAM, altered ␣ 2-integrin cytoplasmic signaling contributes to abnormal cellular behavior in these lung lesions. Aberrant cell adhesion molecule and Hox protein regulation are likely part of the mechanism involved in the development of BPS and CCAM.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

Volpe

Chung²,

Ulm³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…4). Furthermore, rodents treated with the RA inhibitor nitrofen, a common model of CDH-associated pulmonary hypoplasia, showed abnormal expression patterns of HOXA5 in the developing lung buds (55).…”

Section: Discussionmentioning

confidence: 99%

Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes

Russell

Longoni

Wells

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

118

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Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies.

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“…PSEN-1 and YAP expression were examined in whole lung sections from fetal mice of gestation E16, E17, and E18 in a modification of methods we have previously described [32]. Briefly, lungs were fixed in PBS (phosphate buffered saline) containing 4% PFA (paraformaldehyde), pH 7.2, for 4 hours and incubated in PBS with 30% sucrose overnight at 4°C.…”

Section: 0 Methods and Materialsmentioning

confidence: 99%

Presenilin-1 processing of ErbB4 in fetal type II cells is necessary for control of fetal lung maturation

Hoeing

Zscheppang

Mujahid

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Maturation of pulmonary fetal type II cells to initiate adequate surfactant production is crucial for postnatal respiratory function. Little is known about specific mechanisms of signal transduction controlling type II cell maturation. The ErbB4 receptor and its ligand neuregulin (NRG) are critical for lung development. ErbB4 is cleaved at the cell membrane by the γ-secretase enzyme complex whose active component is either presenilin-1 (PSEN-1) or presenilin-2. ErbB4 cleavage releases the 80 kDa intracellular domain (4ICD) which associates with chaperone proteins such as YAP (Yes associated protein) and translocates to the nucleus to regulate gene expression. We hypothesized that PSEN-1 and YAP have a development-specific expression in fetal type II cells and are important for ErbB4 signaling in surfactant production. In primary fetal mouse E16, E17, and E18 type II cells, PSEN-1 and YAP expression increased at E17 and E18 over E16. Subcellular fractionation showed a strong cytosolic and a weaker membrane location of both PSEN-1 and YAP. This was enhanced by NRG stimulation. Co-immunoprecipitations showed ErbB4 associated separately with PSEN-1 and with YAP. Their association, phosphorylation and co-localization were induced by NRG. Confocal immunofluorescence and nuclear fractionation confirmed these associations in a time-dependent manner after NRG stimulation. Primary ErbB4-deleted E17 type II cells were transfected with a mutant ErbB4 lacking the γ-secretase binding site. When compared to transfection with wild type ErbB4, the stimulatory effect of NRG on surfactant protein mRNA expression was lost. We conclude that PSEN-1 and YAP have crucial roles in ErbB4 signal transduction during type II cell maturation.

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Unique spatial and cellular expression patterns of Hoxa5, Hoxb4, and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia

Cited by 21 publications

References 73 publications

Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes

Presenilin-1 processing of ErbB4 in fetal type II cells is necessary for control of fetal lung maturation

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