Expression and Functions of Fibroblast Growth Factor 10 in the Mouse Mammary Gland
Recent molecular genetic and embryonic organ culture studies have implicated several novel regulatory processes in the coordination of lung development. Failure of pulmonary initiation results from interruptions of the sonic hedgehog/patched/Gli and Nkx 2.1 signaling pathways. Sonic hedgehog null mutants and Gli2/Gli3 compound null mutants each exhibited failed tracheoesophageal septation. However, proximodistal epithelial differentiation is disrupted by compound Gli mutation, but is preserved in sonic hedgehog mutants. Null mutation of Nkx 2.1 also abrogates tracheoesophageal septation in association with thyroid and pituitary agenesis. Primary tracheal branching is regulated by fibroblast growth factor-10 signaling; in the murine fibroblast growth factor-10 null phenotype, the lung fails to separate from the foregut and morphogenesis is arrested distal to the trachea. Several genes in the fibroblast growth factor-10 pathway have homologous roles in fruit fly tracheal organogenesis, and corresponding Drosophila mutations yield strikingly similar phenotypes. Recent data also indicate that airway branching can be regulated by vascular endothelial growth factor, suggesting mutual regulation of airway and vascular development. The bases of pulmonary left-right asymmetry and laterality have also been investigated. The transforming growth factor-beta superfamily members Lefty-1, Lefty-2, and nodal comprise a regulatory pathway whose function is required for the development of left-right asymmetry, whereas left-right laterality is dependent on regulation of dynein expression by the transcription factor hepatocyte nuclear factor-4. Terminal lung differentiation is modulated by yet another set of signals. Hoxa5 null mutants exhibit tracheal occlusion and surfactant protein deficiency, whereas fibroblast growth factor receptor-2 and -4 compound null phenotypes include abrogated neonatal alveolization, perturbed alveolar myofibroblast differentiation, and persistent neonatal elastin deposition. These new contributions represent substantial advances toward a comprehensive molecular model of pulmonary development.