The homeodomain transcription factor Ventx2 regulates respiratory progenitor cell number and differentiation timing during Xenopus lung development

Ventx2 is an antennapedia superfamily / NKL subclass homeodomain transcription factor best known for its role in the regulation of early dorsal-ventral pattern during Xenopus gastrulation and in the maintenance of neural crest multipotency. In this work we characterize an unappreciated spatial-temporal expression domain of ventx2 in Xenopus respiratory system epithelial progenitors. We find ventx2 is directly induced by BMP signaling in the ventral foregut prior to nkx2-1, the earliest epithelial marker of the respiratory lineage. Functional studies demonstrate that Ventx2 regulates the number of Nkx2-1/Sox9+ respiratory progenitors induced during foregut development, the timing and level of surfactant protein gene expression, and proper tracheal-esophageal separation. Our data suggest that Ventx2 regulates the balance of respiratory progenitor expansion and differentiation. While the ventx gene family has been lost from the mouse genome during evolution, humans have retained a ventx2-like gene (VENTX) and we lastly discuss how our findings might suggest a possible function of VENTX in human respiratory progenitors.