Xin Sun, University of Wisconsin, Madison, USA (host: D. Iber) - Genetic Control of Upper Airway Patterning - 4:00 pm @ BSSE Misrock seminar room


In this talk, I will present our latest data on the role of the mesenchyme in the development of the respiratory tissues.
In the trachea and bronchi of the mouse, airway smooth muscle (SM) and cartilage are localized to complementary domains surrounding the airway epithelium. Proper juxtaposition of these tissues produces a balance of elasticity and rigidity that is critical for effective air passage. It is unknown how this tissue complementation is established during development. Here we will present data where we dissected the developmental relationship of these tissues by genetically disrupting either SM formation (through Srf inactivation) or cartilage formation (through Sox9 inactivation), and assessed the impact on the remaining tissue. We found that in both the trachea and main bronchi, loss of one lineage led to an increase in cell number of the remaining lineage. However, only in the main bronchi, but not in the trachea, did the loss of one lineage led to a spatial expansion of the remaining lineage. In addition to SM defects, cartilage-deficient tracheas displayed epithelial phenotypes, including decreased basal cell number, precocious Clara cell differentiation, and increased secretoglobin expression. Our results demonstrate that the development of upper airway tissues is closely coordinated. A disruption in the formation of one lineage may have widespread consequences on the collectivefunction of these tissues.
Congenital Diaphragmatic Hernia (CDH) leads all birth defects with the highest death rate (40-62%). An overwhelming cause of lethality is insufficient lung function.Survivors suffer increased susceptibility to respiratory viral infections and asthma. CDH is traditionally viewed to originate from diaphragm malformations. In addition to lung hypoplasia, mechanical compression is thought to also cause pulmonary hypertension, associated with a majority of CDH deaths. Discordant with the diaphragm-centric view, the lung is sometimes also affected on theside of the chest without herniated abdominal organs; the extent of the hernia does not always correlate with the severity of respiratory deficiency. These lines of clinical evidence raise the possibility that the diaphragm may not be the sole primary site of CDH. We will present data from genetic mouse models of CDH with two representative sets of genes that have been implicated in CDH:Roundabout receptor (Robo) and PreB cell leukemia homeobox transcription factor (Pbx). In each model, we recovered evidence for diaphragm independent cause of CDH.

Date: September 27, 2013