Proper development of the respiratory system is crucial to generate adequate surface area for gas exchange. Disruption of respiratory developmental processes can lead to diseases such as pulmonary hypo- or hyperplasia (1 in 4,000 live births) or cystadenomatoid malformations, all of which have serious consequences for human health. Several factors have been identified that lead to respiratory system defects in humans, including mutations in SHH and TTF-1. However, patients with these mutations account for only a small subset of infants born with respiratory distress or respiratory failure, making it crucial to uncover novel signaling pathways important in lung development. Furthermore, these or similar pathways are likely to be reactivated during lung injury repair making them possible targets of clinical therapies. The Hippo signaling pathway is a newly discovered evolutionarily conserved mechanism that regulates organ size, proliferation and cell differentiation in the development of many systems. My preliminary data shows that loss of Lats, an upstream Hippo kinase, leads unexpectedly to smaller lung size and impaired branching morphogenesis. Additionally, Lats mutants have premature expression of type 1 alveolar epithelial cell markers. From these data, I hypothesize the Hippo pathway controls lung epithelial cell behavior by influencing key factors involved in branching morphogenesis and alveolar cell differentiation. This hypothesis will be addressed by pursuing two specific aims: 1) Determine how Hippo signaling controls lung branching morphogenesis and 2) determine how Hippo signaling regulates alveolar epithelial cell differentiation. In each of these proposed aims, I will analyze Hippo pathway mutants to determine the contribution of this pathway in regulating epithelial progenitor behavior in the prenatal and adult lung.
The respiratory system is a complex network of branches necessary for sufficient gas exchange. Congenital disorders resulting from respiratory system defects can lead to lifelong respiratory deficits. This study will provide insight into lung development and repair, which may lead to therapeutic intervention in the human population.
| Nantie, Leah B; Young, Randee E; Paltzer, Wyatt G et al. (2018) Lats1/2 inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing. Development 145: |
