Background

The respiratory lineage in mammals – including the trachea and lung – is specified in the ventral foregut about a day after the endoderm forms during the process of gastrulation. Trachea and lungs of the respiratory lineage consist of an endoderm-derived epithelial sheet surrounded by mesoderm-derived mesenchymal cells. Studies on respiratory and other organ primordia in the foregut such as liver, pancreas, esophagus, and stomach have shown that reciprocal interactions between these two cell lineages are critical for patterning and development of these organs.

Previous work has shown that cell fate specification into respiratory, hepatic, and pancreatic lineages is controlled by external cues from surrounding mesenchyme. Several studies suggested a dosage-dependent role for FGF signaling in this process (Jung et al., 1999[^Jung]; Serls et al., 2005[^Serls]; Calmont et al., 2006[^Calmont]; Wandzioch and Zaret, 2009[^Wandzioch]). Furthermore, canonical Wnt signaling has been proposed to be critical for either the specification or maintenance of the respiratory lineage, respectively (Goss et al., 2009[^Goss]; Harris-Johnson et al., 2009[^Harris-Johnson]).

However, the functional relationship, exact role of these signaling pathways in respiratory lineage specification as well as the temporal sequence of specification from a multipotent endodermal progenitor to respiratory progenitor cell is only poorly understood. Importantly, how each cell senses, interprets and integrates those different signaling cues to make a precise and reproducible cell fate decision has not been addressed so far in this system and is arguably one of the most fundamental questions in current developmental biology and stem cell research.

Aim

The overall goal of my PhD project is to better understand how progenitor cells select a certain cell lineage by interpreting and integrating various external chemical cues. I am using the respiratory lineage specification in the mammalian anterior foregut endoderm as a paradigm.

Experimental strategy

I am using a combination of in vitro chemical genetics in embryo cultures, in vivo spatio-temporally controllable genetic strategies as well as live imaging of lineage- and signaling pathway-specific reporters to obtain single-cell and, if possible, time-resolved data to analyze how signals from the FGF, BMP and Wnt/β-catenin pathways are integrated and computed on a cellular and population level to specify respiratory progenitors. These quantitative data will be the basis for mathematical models with which I hope to gain mechanistic insights into this process.