ORMDL deregulation

The risk for asthma is determined by environmental and genetic factors. Exposure to cigarette smoke in early life is an established exogenous risk factor for childhood asthma, while ORMDL3 is an important asthma risk gene within the 17q21 locus. Their interaction, however, remains unclear. To investigate this, we used D. melanogaster lines with airway-specific ORMDL overexpression (OE) or knockdown (KD). Larvae were exposed to 3 puffs/min of 3R4F research cigarettes for 1 h/day over three days. Airway morphology, crawling distance, and larval size/weight were measured thereafter. RNA-sequencing (RNASeq) of isolated airways was analyzed for altered developmental pathways. The main findings were an increased airway epithelial thickness and smaller terminal cells (alveolar equivalents) in ORMDL-OE animals that were additionally exposed to CS. Compromised airway development was accompanied by slower crawling speed and reduced weight and length of larvae. RNASeq revealed dysregulation of evolutionarily highly conserved genes within wnt, notch, and dopamine signalling pathways, which are central to airway development, as well as genes related to basal membrane integrity in ORMDL-OE animals that were further altered by CS. These findings suggest that ORMDL heightens airway sensitivity to CS, causing greater developmental impairment than either factor alone. We propose that D. melanogaster provides a powerful model for investigating changes of the airway structure and evolutionarily conserved pathways in response to environmental toxins, which is ethically impossible to study in infants.