Lung biology and FGF9 signaling.

Congenital diaphragmatic hernia (CDH) has an incidence of 1:2700 live births. In this disease, abdominal viscera herniate into the thoracic cavity early in gestation, inhibiting normal fetal lung growth and development. Pathophysiological consequences of CDH, such as pulmonary hypertension, surfactant deficiency, and left ventricular hypoplasia, may act synergistically to produce a mortality exceeding sixty percent. Infants that survive CDH often suffer from severe chronic lung disease, developmental delay and growth retardation.

Bronchopulmonary dysplasia (BPD) is a disease that is seen primarily in preterm newborns. The pathogenesis of BPD involves extreme lung immaturity. Severely affected infants have a long-term global reduction in alveolar number and surface area. This phenotype is consistent with an inhibition or arrest of normal lung maturation (at the cananicular stage of development). BPD is also associated with widespread interstitial fibrosis resulting from repeated lung injury and disorganized repair. For infants that survive, long-term consequences of BPD include decreased pulmonary capacity (decreased alveolar area) and interstitial fibrosis.

FGF9 is expressed in the mesothelial lining of the lung throughout embryonic development. Additionally, at early stages of development, FGF9 is also present in respiratory epithelium. Given the location of Fgf9 expression, we hypothesize that it could respond to forces that influence lung size and shape and could function to regulate lung size and shape. We have established that FGF9 is a critical regulator of lung mesenchyme growth. We have shown that mice lacking Fgf9 have a severe defect in lung growth, that Fgf9 is expressed in human fibrotic lung tissue and that Fgf9 expression is induced in a rat post pneumonectomy lung regeneration model. Overexpression of FGF9 in the developing mouse lung results in increased mesenchymal growth and an arrest of branching morphogenesis.

Current projects focus on receptors that mediate FGF9 signaling in lung mesenchyme and the reciprocal signaling relationship between mesenchymal FGF and Wnt pathways. Understanding lung mesenchyme development is important because lung mesenchyme determines the shape and size of the maturing lung by providing a substrate for epithelial growth and providing cues for patterning and development of the epithelial branching structure of the lung. Lung mesenchyme also gives rise to peribronchiolar smooth muscle and serves to support vascular development, which is essential for the gas exchange function of the lung.

Related publications:
Colvin, J.S., Feldman, B., Nadeau, J.H., Goldfarb, M., and Ornitz, D.M. (1999). Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev Dyn 216, 72-88.

Colvin, J.S., White, A., Pratt, S.J., and Ornitz, D.M. (2001). Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128, 2095-2106.

White, A.C., Xu, J., Yin, Y., Smith, C., Schmid, G., and Ornitz, D.M. (2006). FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development 133, 1507-1517.

White, A.C., Lavine, K.J., and Ornitz, D.M. (2007). FGF9 and SHH Regulate Mesenchymal Vegfa Expression and Development of the Pulmonary Capillary Network. Development 134, 3743-3752.