Grainy head-like 2: a critical regulator of lung morphogenesis

A Kersbergen1, SA Best1, M De Vries2, ME Ritchie1, SM Jane2, S Dworkin3 and KD Sutherland1

  1. Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research
  2. Department of Medicine, Monash University Central Clinical School
  3. Department of Physiology, Anatomy and Microbiology, La Trobe University

The lung is composed of a highly branched network of conducting airway tubes and distal alveoli. The process of lung morphogenesis is tightly controlled by both growth factors and transcription factors. One family of transcription factors which is of interest in the context of lung development, is the Grainy head-like (Grhl) family (Grhl1-3). In Drosophila, the antecedent member of the Grhl family, grainyhead (grh), contributes to tracheal organogenesis and in mammals, grh homologues regulate numerous developmental processes, including neural tube closure, epidermal barrier formation and wound healing, neural apoptosis and brain morphogenesis, and craniofacial development. In the context of lung development in the mouse, Grhl2 exhibits the earliest, strongest and most persistent expression levels among family members. However, as mice lacking Grhl2 (Grhl2-/-) succumb to embryonic lethality by E11.5, we are unable to examine lung development past this stage. To explore a role for Grhl2 in lung development we crossed Grhl2flox/- mice with mice carrying either the Shh-Cre allele or the Sox17-iCre allele. Analysis of Grhl2 conditional knockout mice reveal critical roles for Grhl2 in tracheal/lung development, as mice lacking Grhl2 die within hours of birth due to respiratory distress. Putative Grhl2 target genes, which may be effectors of Grhl2 function in the context of respiratory development, have been identified by RNA-seq on isolated epithelial cells from Grhl2 mutant and control embryonic lungs. This study has identified Grhl2 as a master regulator of lung morphogenesis.