Developmental Pathways Underlying Lung Development and Congenital Lung Disorders

Abstract

Lung organogenesis is a highly coordinated process governed by a network of conserved signaling pathways that ultimately control patterning, growth, and differentiation. This rigorously regulated developmental process culminates with the formation of a fully functional organ. Conversely, failure to correctly regulate this intricate series of events results in severe abnormalities that may compromise postnatal survival or affect/disrupt lung function through early life and adulthood. Conditions like congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchogenic cysts, and congenital diaphragmatic hernia display unique forms of lung abnormalities. The etiology of these disorders is not yet completely understood; however, specific developmental pathways have already been reported as deregulated. In this sense, this review focuses on the molecular mechanisms that contribute to normal/abnormal lung growth and development and their impact on postnatal survival.

Keywords: bronchogenic cysts; bronchopulmonary sequestration; congenital diaphragmatic hernia (CDH); congenital malformations; congenital pulmonary airway malformation (CPAM).

Figure 1

Summary of the molecular players involved in lung specification. A BMP gradient elicits dorsal SOX2 expression (esophageal progenitors) vs. ventral NKX2.1 expression (respiratory progenitors). Yellow, endoderm; blue, mesoderm.

Figure 2

Signaling pathways that mediate epithelial–mesenchymal interactions during pseudoglandular stage, specifically in the distal epithelial tip. SOX2+ cells define proximal epithelial cell lineages whereas SOX9+ cells define distal epithelial cell lineages. Yellow, epithelium; blue, mesenchyme.

Figure 3

Simplified representation of the signaling pathways implicated in the canalicular stage. Proximal SOX2+ cells generate conducting airway cells (neuroendocrine, secretory, multiciliated and basal). Distal SOX9+ cells generate alveolar epithelial cells.

Figure 4

Simplified scheme of the signaling pathways involved in alveolar epithelial cell type 1 (AEC1) and type 2 (AEC2) differentiation during the saccular stage. Blue label: AEC1 differentiation; red label: AEC2 differentiation. (miR), present in the lung compartment.

Figure 5

Schematic representation of the signaling events occurring during alveologenesis, particularly secondary septa formation. Left image: alveolar niche. Right image: magnification of the secondary septa.