Goncharova et al. (2014) investigated the role of FLCN in the lungs using a mouse model where FLCN has been specifically deleted in alveolar epithelial type II cells (AECs). These mice showed pulmonary developmental defects and impaired lung function consistent with a role for FLCN in branching morphogenesis. Mice with FLCN deleted in lung epithelial cells did not show any such developmental defect or loss of lung function, indicating that this phenotype is specifically caused by loss of FLCN function in AECs.
Loss of FLCN in AECs led to increased apoptosis and cell permeability due to loss of E-cadherin expression, subsequent LKB1 dysregulation and consequent AMPK downregulation. The AMPK activator, AICAR, and constitutively active AMPK were able to increase cell survival in FLCN-null cells, and AICAR improved alveolar surface tension in vivo. Loss of FLCN also led to an increased inflammatory response in vivo, as measured by increased MMP3 and MMP9 expression, which was also reversed by AICAR.
This study suggests that FLCN promotes cell survival and the assembly of epithelial cell junctions via the E-cadherin-LKB1-AMPK signalling axis, and suppresses inflammation, and is thus required for correct lung physiology and function.
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This research was partly funded by the Myrovlytis Trust.