Gene regulatory networks governing lung specification

Abstract

The epithelial lining of the respiratory system originates from a small group of progenitor cells in the ventral foregut endoderm of the early embryo. Research in the last decade has revealed a number of paracrine signaling pathways that are critical for the development of these respiratory progenitors. In the post-genomic era the challenge now is to figure out at the genome wide level how these different signaling pathways and their downstream transcription factors interact in a complex "gene regulatory network" (GRN) to orchestrate early lung development. In this prospective, we review our growing understanding of the GRN governing lung specification. We discuss key gaps in our knowledge and describe emerging opportunities that will soon provide an unprecedented understanding of lung development and accelerate our ability to apply this knowledge to regenerative medicine.

Keywords: GENE REGULATORY NETWORK; LUNG DEVELOPMENT; Nkx2.1; RESPIRATORY EPITHELIUM; SPECIFICATION.

Figure 1. Development of Nkx2.1-expressing respiratory progenitors

A) Three-dimensional confocal immunostaining of an E9.5 mouse embryo showing the Foxa2-expressing primitive gut tube (yellow) with Nkx2.1 expression (magenta) in the respiratory progenitors and thyroid primordial. The colored image of the gut tube is superimposed on the epifluorescent image of the embryo in gray scale. B) A lineage diagram showing that the epithelial cells lining the trachea and lungs develops from respiratory progenitors in the ventral foregut of the early embryo. These respiratory progenitors arise from multipotent foregut endoderm cells that also contribute to the digestive system. Segregation of the epiblast into endoderm, mesoderm and ectoderm germ layers occurs during gastrulation. N.E.; neuroendocrine

Figure 2. The GRN controlling respiratory specification

A–B) Confocal immunostaining of a cross section through the foregut a E9 mouse embryo (A) and a two-day-old (E2) Xenopus embryo (B). Nkx2.1⁺ lung progenitors (red) are located in the ventral foregut, whereas Sox2⁺ esophagus progenitors (eso) are restricted to the dorsal foregut. The surrounding splanchnic mesenchyme expresses the transcription factor Foxf1 (green). C) A diagram of the foregut showing the spatial arrangement of paracrine factors regulating respiratory specification and D–V patterning of the foregut. Differential Wnt and BMP signaling results in a gradient of β-catenin and pSmad1 activity in the epithelium, highest in the Nkx2.1⁺ ventral foregut and lowest in the Sox2⁺ dorsal foregut. D) A diagram of the evolutionarily conserved GRN controlling specification of the respiratory progenitors. This model represents gene interactions data from the published literature combining results from mouse, chicken and Xenopus embryos. Orange lines indicate Xenopus data, which remain to be tested in other species. Dashed lines indicate relationships that are only weekly supported; mostly inferred from in vitro data. The epithelial compartment is indicated in the blue-red gradient, whereas gene expressed in the mesenchymal compartment is in the green area. The light box highlights the core Wnt/BMP regulatory cassette immediately upstream of foregut patterning and specification of the respiratory progenitors.