Impact of the loss of Hoxa5 function on lung alveogenesis.
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.
Mandeville
Isabel
I
Centre de Recherche de L'Hôtel-Dieu de Québec, 9, rue McMahon, Québec, QC, Canada, G1R 2J6.
Aubin
Josée
J
LeBlanc
Michelle
M
Lalancette-Hébert
Mélanie
M
Janelle
Marie-France
MF
Tremblay
Guy M
GM
Jeannotte
Lucie
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D004549:Elastin / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000002:abnormalities / Q000737:chemistry / Q000254:growth & development; D008171:Lung Diseases / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009929:Organ Size / Q000235:genetics; D038081:Organogenesis / Q000235:genetics*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000002:abnormalities* / Q000737:chemistry / Q000254:growth & development*; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors
D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D004549:Elastin