Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function

Kinkead, Richard; LeBlanc, Michelle G.; Gulemetova, Roumiana; Lalancette–Hébert, Mélanie; Lemieux, Margot; Mandeville, Isabel

doi:10.1203/01.pdr.0000139427.26083.3d

Cited by 21 publications

(27 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…27 Surviving adult mutants present a severe emphysemalike phenotype characterized by enlarged airspaces and an overall decrease in septa number. 28 On macroscopic examination, some areas of Hoxa5 Ϫ/Ϫ lungs were completely depleted of alveoli, whereas others showed large tubular structures (shown for P31; Figure 1, K and L). To assess the origin of the morphological defects, lung histological analyses were performed at different ages after birth.…”

Section: Abnormal Lung Morphology In Hoxa5mentioning

confidence: 95%

“…26 The analysis of the Hoxa5 mutant mouse line has revealed the preponderant role of this gene in lung development and maturation. 27,28 The loss of Hoxa5 function severely compromises viability at birth because of trachea and lung dysmorphogenesis. Moreover, the Hoxa5 mutation affects the embryonic expression of epithelial regulators of lung development and function, such as the Nkx2.1, Foxa2, and N-myc genes.…”

Section: Hoxa5mentioning

confidence: 99%

“…Hoxa5 is still strongly expressed in postnatal lung, and surviving Hoxa5 Ϫ/Ϫ adults present lung anomalies with deficient alveolar septation and atelectasis. 28,29 These anatomical limitations impact on the breathing pattern of Hoxa5 Ϫ/Ϫ mice that compensate for their decreased alveolar surface area available for gas exchange by an increase in breathing frequency and overall minute ventilation. In humans, aberrant HOXA5 expression has been shown to correlate with lung diseases.…”

Section: Hoxa5mentioning

confidence: 99%

“…The postnatal lung phenotype of Hoxa5 Ϫ/Ϫ mutants bears some similarities with that of Pdgfa Ϫ/Ϫ mutants including emphysema morphology and atelectasis. 7,11,28 However, the etiology of impaired alveogenesis in Hoxa5 mutants differs from that of Pdgfa Ϫ/Ϫ mice. Alveolar myofibroblasts are lacking in Pdgfa Ϫ/Ϫ lungs, whereas they are mispositioned in Hoxa5 Ϫ/Ϫ postnatal lungs.…”

Section: Contribution Of Altered Cell Specification To Impaired Alveomentioning

confidence: 99%

“…Hoxa5 Ϫ/Ϫ mutants adapt their respiratory behavior and present a modified breathing pattern to compensate for the emphysematous morphology. 28 When parameters of respiratory mechanics are measured in Hoxa5 Ϫ/Ϫ mutants, they reveal a decreased lung hysterisivity, a species-independent constant corresponding to the ratio between resistance and elastance of alveolar parenchyma (not shown). 58 The change in hysterisivity in Hoxa5 Ϫ/Ϫ mutants reflects the structural lung anomalies.…”

Section: Relevance Of Hox Genes To Pulmonary Diseasesmentioning

confidence: 99%

See 4 more Smart Citations

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Abnormal Lung Morphology In Hoxa5mentioning

confidence: 95%

Section: Hoxa5mentioning

confidence: 99%

Section: Hoxa5mentioning

confidence: 99%

Section: Contribution Of Altered Cell Specification To Impaired Alveomentioning

confidence: 99%

Section: Relevance Of Hox Genes To Pulmonary Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

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

Volpe

Wang

Nielsen

et al. 2008

Birth Defects Research

View full text Add to dashboard Cite

Background-Hox transcription factors modulate signaling pathways controlling organ morphogenesis and maintain cell fate and differentiation in adults. Retinoid signaling, key in regulating Hox expression, is altered in pulmonary hypoplasia. Information on pattern-specific expression of Hox proteins in normal lung development and in pulmonary hypoplasia is minimal. Our objective was to determine how pulmonary hypoplasia alters temporal, spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 proteins compared to normal lung development.

show abstract

Stromal Hoxa5 function controls the growth and differentiation of mammary alveolar epithelium

Garin

Lemieux

Coulombe

et al. 2006

Developmental Dynamics

Self Cite

View full text Add to dashboard Cite

Recent progress has enlightened the involvement of Hox genes in organogenesis. Several Hox genes are expressed in normal and neoplastic mammary glands. Using Hoxa5 mutant mice, we showed that Hoxa5 Ϫ/Ϫ females present nursing defects. Characterization of the Hoxa5 Ϫ/Ϫ mammary gland phenotype reveals changes in proliferation and differentiation of the epithelium of nulliparous and pregnant Hoxa5 Ϫ/Ϫ females that precede the abnormal secretory activity at parturition. These defects likely underlie the incapacity of Hoxa5 Ϫ/Ϫ dams to properly feed their pups. Hoxa5 expression is restricted to the mammary stroma at specific stages of mammary gland development. The loss of Hoxa5 function causes accelerated lobuloalveolar epithelium development, a phenotype that can be rescued upon grafting of mutant mammary epithelium into wild-type fat pads. Conversely, reciprocal grafting experiments demonstrate that Hoxa5 Ϫ/Ϫ stroma cannot support normal proliferation of wild-type mammary epithelium. These data establish the essential contribution of Hoxa5 to mammary epithelium instruction by means of mesenchymal-epithelial crosstalk.

show abstract

Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function

Cited by 21 publications

References 46 publications

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

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

Stromal Hoxa5 function controls the growth and differentiation of mammary alveolar epithelium

Contact Info

Product

Resources

About