Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Abstract

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.

Unsuspected effects of a lung‐specific cre deleter mouse line

“…In these animals, the lung phenotype was also comparable to the one seen in Sftpc-cre mice and it completely differed from the lung phenotype normally observed in Hoxa5 2/2 mice ( Fig. 4d,f; Mandeville et al, 2006). Even though we cannot rule out the possibility that the Sftpc-cre-associated phenotype may mask some effect of the deletion of Hoxa5 in the lung epithelium, our data suggested that the specific deletion of Hoxa5 gene function in lung epithelium does not affect lung development.…”

“…The complete loss of Hoxa5 function severely compromises viability at birth due to trachea and lung dysmorphogenesis, while surviving Hoxa5 2/2 adults present lung anomalies with deficient alveolar septation and atelectasis (Aubin et al, 1997;Kinkead et al, 2004;Mandeville et al, 2006). Our previous work has demonstrated that Hoxa5 expression is restricted to lung mesenchyme (Aubin et al, 1997;not shown).…”

Comparative spatiotemporal analysis of Hox gene expression in early stages of intermediate mesoderm formation

“…Loss of Hox genes has been found in certain cases to result in the loss of particular tissues (Lovegrove et al, 2006;Mandeville et al, 2006;Hostikka et al, 2009;Le Pabic et al, 2010). There is some evidence indicating the role of Hox genes during kidney development (reviewed by Patterson and Potter, 2003;Costantini and Kopan, 2010;Wellik, 2011).…”

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

“…These studies indicate that Hoxb5 and Hoxa5 impact airway and alveolar development through cell-cell communication between the mesenchyme and epithelial cell compartments, but the exact mechanisms by which this occurs is not yet completely understood. (Aubin et al 1997;Volpe et al 1997, Golpon et al 2001Volpe et al 2003;Kinkead et al 2004;Mandelville et al 2006;Volpe et al 2007Volpe et al , 2008). An essential role played by mesenchyme to epithelial cell communication within the developing lung is the control of vessel formation within the lung mesenchyme that drives airway and alveolar development.…”