We study the development and function of the mammalian lung. We use genetic tools in mouse to dissect the function of developmental signaling pathways in formation of the lung and their contribution to lung disease.
Initiation of the respiratory lineage
The mammalian respiratory system, consisting of both the trachea and lung, arises from the ventral foregut endoderm. In contrast, the anterior digestive tract, namely the esophagus and stomach, emerges from the dorsal foregut endoderm. Defects in either the specification of the respiratory lineage, or the subsequent morphogenetic events that separate it from the digestive tract, result in failure to breathe at birth. Trachea-esophagus associated defects occur in approximately 1 in 3,500 birth. The high mortality and morbidity associated with these defects pose a significant challenge in pediatric medicine.
Figure 1. Foregut development.
(A) Diagrams of the foregut depicting the two steps (specification and morphogenesis) that establish the separate lineages. Dashed line indicates the section plane shown in B. (B) Immunostaining of transverse sections of mouse foregut with key markers of the lineages, NKX2.1 (trachea/lung) and SOX2 (esophagus). Abbreviations: An, anterior; D, dorsal; es, esophagus, lu, lung; Po, posterior; sto, stomach; tr, trachea; V, ventral. Modified from Que et al., 2006.
We use mouse models to understand the genetic control underlying the establishment of the trachea/lung versus esophagus/stomach primordia. The embryonic foregut is a hub for developmental signals, including WNT, FGF, BMP and SHH. We have focused on dissecting their roles in the specification of respiratory versus digestive progenitors (Harris-Johnson et al., 2009). Based on the similarities between these progenitors (e.g. respiratory progenitors) and adult organ stem cells (e.g. lung stem cells), our findings may inform efforts to generate and manipulate these stem cells.
Lung outgrowth and patterning
After the initiation of lung buds, lung branching morphogenesis ensues to give rise to an elaborate respiratory tree essential for breathing. We use genetic tools to understand how developmental signals (e.g. FGF10) drive epithelial growth and branching (Abler et al., 2009), as well as how these signals are regulated (e.g. by Dicer and microRNAs) (Harris et al., 2006). In the lung mesenchyme, precise patterning of smooth muscles and vasculature is critical for the construction of a functional lung. Our genetic data suggest that signals such as FGF9 maintains an undifferentiated zone in the distal mesenchyme that serves as a continuing source of smooth muscle progenitors in lung (Yi et al., 2008).
Figure 2. Progression of lung development.
Images of transgenic mouse lungs (left three panels) and a diagram (right panel) to illustrate the three steps of lung development. In the transgenic lungs, the epithelium is outlined by ß-galactosidase (ß-gal, blue) staining. The diagram depicts the differentiation within an alveolus, formed from one of the branching tips.
In addition to signaling molecules, we also investigate the role of transcription factors in lung development. Using a cDNA collection that represents approximately 80% of all transcription factors encoded in the mouse genome, we carried out a large-scale in situ hybridization screen to explore the expression patterns of 1,100 transcription factors. We identified 60 transcription factors expressed in spatially restricted manner in the embryonic lung. Our current focus is to systematically address their possible involvement in lung morphogenesis, patterning and differentiation.
Figure 3. Expression of transcription factors in embryonic lung.
Future directions in lung research
The general goals of our future research in lung are to identify further links between developmental signals and their cellular output, and to directly apply our findings to better understand lung disease mechanisms. One focus is to address crosstalk of signaling pathways during respiratory initiation. The clear readouts of the developmental outcome establish the foregut as an ideal setting to dissect pathway relationships. A second focus is to understand how the fetal lung and immune system interact in the process of organ maturation. We are part of a multidisciplinary team, working with pulmonary allergists, virologists, physiologists and biostatisticians to investigate how viral infections in the neonatal period may impact lung development and long-term lung function. As the immune system and lung interactions are bidirections, we are also addressing how deviations from normal lung development contributes to increased susceptibility to respiratory infections and chronic diseases such as asthma.