Cardoso Lab – Research
Basic Science Research
Retinoic acid signaling in lung development:
Disruption of retinoic acid (RA) signaling in Vitamin A deficient embryos results in major developmental abnormalities including tracheoesophageal fistula, lobation defects, lung hypoplasia and, in its severest form, failure to form lungs. Our studies reveal that RA signaling is highly active at the onset of lung development. We are using RA reporter (RARElacZ) and RA deficient (Retinaldehyde dehydrogenase-2 -/-) mouse lines, as well as pharmacological inhibitors of RA signaling (BMS493) to identify RA-dependent pathways critical for initiation of lung development. We have recently identified an important role for RA in controlling Tgf beta signaling and Fgf10 expression in the foregut during formation of the lung primordium.
Fgf10 regulation of lung progenitor cell expansion and bud formation:
>Local expression of Fgf10 in the foregut mesoderm is required to activate Fgfr2b signaling in lung epithelial progenitors and form the lung primary buds. Fgf10 null mice form trachea but not the lung. We have been studying mechanisms that regulate Fgf10 expression at the onset of lung development and during branching morphogenesis. We have identified by genome-wide screen and are currently characterizing a number of Fgf10 targets, including genes involved in cell rearrangement, cell migration and proliferation, proteolysis and other functions.
FGF-heparan sulfate interactions in lung epithelial morphogenesis:
Heparan sulfate (HS) proteoglycans modulate the biological activity of a number of growth factors Fgf, Wnt, and Tgf beta in development, homeostasis and cancer. We have been studying the role of HS sulfation mediated by HS 6-O sulfotransferases (Hs6st) in pre- and postnatal lung development. We have developed in vitro models to study how HS modifications influence Fgf signaling and patterning of embryonic lung explants. We also have generated a Hs6st1 knock mouse model for in vivo studies.
Notch signaling in the early lung:
Studies in a number of biological systems show that Notch signaling controls cell fate decisions, establishment of asymmetries, and timing of differentiation. We are exploring the role of Notch in the developing respiratory epithelium at early stages. Our studies show that Notch signaling is required to balance proximal-distal cell fates and for the establishment of proper morphogenetic boundaries in developing airways.
