Table 1.
Summary of the molecular players and corresponding major events underlying normal lung development.
| Stage | Major Events | Molecular Players | Expression Site | Function |
|---|---|---|---|---|
| Embryonic | Lung bud develops from the foregut; Tracheoesophageal septation |
NKX2.1 (or TTF1) | Endoderm | Specification of respiratory progenitors Epithelial marker |
| TBX4 | Mesoderm | Induction of endodermal differentiation (nkx2.1-dependnent) & budding (fgf10-dependent) |
||
| WNT2/2B | Mesoderm | Specification of NKX2.1 respiratory progenitors | ||
| GATA4/6 | Endoderm | Formation of primary lung structures Differentiation of visceral endoderm |
||
| SHH/ GLI1-3 |
Endoderm/ Mesoderm |
Embryonic foregut development | ||
| FOXF1 | Mesoderm | Lung & gastrointestinal morphogenesis Regulation of mesenchymal-epithelial interactions |
||
| FOXA1/A2 | Endoderm | Specification of foregut endoderm Branching morphogenesis |
||
| Pseudoglandular | Formation of bronchial buds: Branching morphogenesis. Formation of bronchial tree and blood vessels; Cellular differentiation (cartilage, smooth muscle); |
FGF10/ FGFR2 |
Mesenchyme/ Epithelium |
Lung bud outgrowth |
| SPRY2 | Distal epithelium | Negatively regulates FGF10 signaling Inhibits lung budding |
||
| TGFβ | Mesenchyme/ Epithelium |
Lung branching | ||
| BMP4 | Epithelium of distal tips | Negatively regulates FGF10 signaling Inhibits lung budding |
||
| SHH | Epithelium | Branching morphogenesis | ||
| RDH10 | Lung buds | Lung bud outgrowth | ||
| RALDH2 | Mesothelial region | Lung growth and branching | ||
| WNT7B | Distal epithelium | Branching morphogenesis | ||
| WNT2A | Distal lung mesothelium | Mesenchymal cell proliferation | ||
| WNT5A | Mesenchyme/ Epithelium |
Tracheal development/ Distal lung morphogenesis |
||
| β-Catenin | Airway epithelium | Branching morphogenesis Epithelial differentiation and proliferation |
||
| HOXB5 | Mesenchyme | Anterior-posterior patterning Directing epithelial morphogenesis |
||
| SOX2 | Proximal epithelium | Proximal-distal patterning | ||
| SOX9 | Distal epithelium | Proximal-distal patterning | ||
| miR-17 miR-20a miR-106b |
Epithelium | FGF10-mediated epithelial branching morphogenesis | ||
| miR-200b | Epithelium & Mesenchyme |
Distal airway branching | ||
| miR-449a | Distal epithelium | Regulation of differentiation & proliferation | ||
| miR-326 | Mesenchyme | SHH signaling modulator | ||
| miR-142-3p | Mesenchyme | Proliferation & differentiation of mesenchymal progenitors Control of WNT signaling |
||
| Canalicular | Formation of distal most airways; Alveolar cellular differentiation; Appearance of the first air-blood barrier; Surfactant production initiation |
NOTCH | Determination of cellular fate Development of microvasculature network |
|
| miR-449a | Distal epithelium | Regulation of differentiation & proliferation | ||
| Saccular | Formation of thin-walled terminal saccules (alveoli precursors); Maturation of vasculature and surfactant system |
RARα | Epithelium | Sacculation & differentiation of mature AEC1 |
| RARβ | Epithelium | AEC1 & AEC2 induction | ||
| miR-26a-1/ miR-26a-2 |
Alveolar epithelial cells |
Pulmonary surfactant synthesis | ||
| miR-17-92 | Epithelium | AEC1 remodeling | ||
| Alveolar | Alveologenesis: establishment of secondary septa and alveoli formation; Microvascular maturation: single-layered capillary network formation. |
VEGF-A | Epithelium | Vascular development |
| PDGF-A/ PDGFRα/β |
Epithelium/ Mesenchyme |
Myofibroblast differentiation Elastin production Secondary septation & alveolarization |
||
| Ephrin-B2 | Microvasculature | Secondary septation & alveolarization | ||
| miR-34a | Impairs alveolarization | |||
| miR-29b | Promotes alveolarization | |||
| miR-876-3p | Promotes alveolarization | |||
| miR-421 | Alveolar epithelial cells | Disrupts alveolarization |