Hoxb-5 control of early airway formation during branching morphogenesis in the developing mouse lung

Volpe, MaryAnn V.; Vosatka, Robert J.; Nielsen, Heber C.

doi:10.1016/s0304-4165(00)00087-8

Cited by 39 publications

(55 citation statements)

References 39 publications

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“…Antibodies: Hoxb5 rabbit polyclonal antibody was produced and characterized in our laboratory (Volpe et al 2000). E-Cadherin rat monoclonal antibody was purchased from Invitrogen, (Grand Island, NY).…”

Section: Reagentsmentioning

confidence: 99%

“…Control lungs grew at a consistent rate from 48 through 96 h of culture (Bogue et al 1994;Aubin et al 1997;Volpe et al 1997Volpe et al , 2000Volpe et al , 2003, we evaluated Hoxb5 and Hoxa5 protein levels and immunolocalization in lungs from the RA and O 2 groups. After 48 h of 0.4 FiO 2 , Hoxb5 protein levels decreased to 50% of control lungs ( Fig.…”

Section: Fio 2 Altered Lung Morphologic Developmentmentioning

confidence: 99%

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Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

Silfa-Mazara

Mujahid

Thomas

et al. 2014

Journal of Cell Communication and Signaling

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Hoxb5 and Hoxa5 transcription factor proteins uniquely impact lung morphogenesis at the developmental time point when extremely preterm infants are born. The effect of O 2 exposure (0.4 FiO 2 ) used in preterm infant care on these Hox proteins is unknown. We used ex vivo fetal mouse lung organ cultures to explore the effects of 0.4 FiO 2 on lung airway and vascular formation in the context of Hoxb5 and Hoxa5 expression and regulation. Compared to room air, 48 h (h) 0.4 FiO 2 adversely attenuated airway and microvasculature formation while reducing lung growth and epithelial cell volume, and increasing mesenchymal volume. 0.4 FiO 2 decreased pro-angiogenic Hoxb5 and VEGFR2 while not altering protein levels of angiostatic Hoxa5. Lungs returned to RA after 24 h 0.4FiO 2 had partial structural recovery but remained smaller and less developed. Mesenchymal cell apoptosis increased and proliferation decreased with time in O 2 while epithelial cell proliferation significantly increased. Hoxb5 overexpression led to prominent peri-airway VEGFR2 expression and promoted lung vascular and airway patterning. Hoxa5 overexpression had the opposite effects. We conclude that 0.4 FiO 2 exposure causes a profound loss of airway and lung microvascular development that occurs partially via reduction in pro-angiogenic Hoxb5 while angiostatic Hoxa5 expression is maintained.

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Section: Reagentsmentioning

confidence: 99%

Section: Fio 2 Altered Lung Morphologic Developmentmentioning

confidence: 99%

Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

Silfa-Mazara

Mujahid

Thomas

et al. 2014

Journal of Cell Communication and Signaling

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“…23 Although no lung phenotype has been reported in Hoxb5 Ϫ/Ϫ mice, 24 abnormal Hoxb5 expression correlates with alterations in bronchiolar branching. 25 Moreover, the HOXB5 gene was found aberrantly expressed in patients suffering from bronchopulmonary sequestration and congenital cystic adenomatoid malformation. 26 The analysis of the Hoxa5 mutant mouse line has revealed the preponderant role of this gene in lung development and maturation.…”

Section: Hoxa5mentioning

confidence: 99%

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

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The involvement of genes controlling embryonic processes in the etiology of diseases often escapes attention because of the focus given to their inherent developmental role. Hoxa5 belongs to the Hox gene family encoding transcription factors known for their role in skeletal patterning. Hoxa5 is required for embryonic respiratory tract morphogenesis. We now show that the loss of Hoxa5 function has severe repercussions on postnatal lung development. Hoxa5؊/؊ lungs present an emphysema-like morphology because of impaired alveogenesis. Chronic inflammation characteristics, including goblet cell hyperplasia, mucus hypersecretion, and recruitment of inflammatory cells, were also observed. Altered cell specification during lung morphogenesis triggered goblet cell anomalies. In addition, the defective motility of alveolar myofibroblast precursors in the embryonic lung led to the mispositioning of the alveolar myofibroblasts and to abnormal elastin deposition postnatally. Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5 ؊/؊ lungs. They constituted an attractive stimulus to recruit activated macrophages that in turn generated a positive feedback loop that perpetuated macrophage accumulation in the lung. The present work corroborates the notion that altered Hox gene expression may predispose to lung pathologies. Lung morphogenesis relies on finely orchestrated processes that initiate from the outpocketing and the elongation of the foregut endoderm into the surrounding mesenchyme. The lung bud then branches extensively giving rise to saccules that expend and subdivide to ultimately produce alveoli. In the mouse, the main stem bronchi form at approximately embryonic day (E) 9.5, and ramification organized by signaling centers shapes the respiratory tree during the pseudoglandular period that extends from E14.0 to E16.5. At late gestational stages, saccules are found at the end of each terminus of the pulmonary tree. The last step of lung morphogenesis occurs between postnatal day (P) 5 and P30, and it aims at multiplying the respiratory surface for vital gas exchanges after birth by modifying the distal lung architecture through the process of alveogenesis. During each step of lung development, the concerted action of transcriptional regulators, signaling molecules, their associated receptors and downstream effectors governs branching morphogenesis and lung maturation by integrating cellular proliferation, differentiation, apoptosis, and migration.

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“…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%

“…This suggests that Hox genes that help determine embryonic and organ-specific patterning evolved along with integrins that help recognize cellcell and cell-matrix interactions coordinating cell positioning and cellular communication in developing and mature organs and tissues (13,28,63). In mice, we have reported that regulated spatial and temporal expression of the Hox protein, Hoxb5, helps regulate airway branching patterns partially through regulation of cell matrix molecules (57,60,61). We have also shown that HoxB5 (nomenclature for human Hoxb5) is expressed in human lung development in a similar pattern to that seen in mouse and that human BPS and CCAM tissue has abnormally high levels of HoxB5 protein, analogous to the canalicular stage of lung development and significantly increased over age and lung development stage-matched controls (59,64).…”

mentioning

confidence: 99%

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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Hoxb-5 control of early airway formation during branching morphogenesis in the developing mouse lung

Cited by 39 publications

References 39 publications

Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

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

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