Paladin or Pald1 is a phosphatase-domain containing protein and was identified in two independent screens for novel regulators of angiogenesis and vascular function. In a collaboration with colleagues in Sweden, the German Mouse Clinic characterized the new Pald1−/− mouse model performing behavioral, physiological and biochemical tests. Most of the phenotypes were not altered for Pald1−/− mice, but female Pald1−/− mice exhibited increased lung volumes and compliance and decreased resistance. It is known, that these parameters are changed in elastase-induced emphysema mouse models. The authors did further experiments to analyze and explain the observed obstructive lung phenotype in this mouse model. They learned that the lack of Pald1 leads to enlarged distal airspaces in female mice, possible linked to the observed reduction of the number and the increased apoptosis and proliferation of the endothelial cells in knock out lungs. The characterization of the lung defects leads Pald1 to sex-specific endothelial cell apoptosis, development of emphysema and COPD-like changes in females. In humans, there are sex-specific differences in COPD and emphysema where subsets of women develop more severe emphysema than men and it has also been shown that female mice develop earlier and more severe emphysema than male mice in response to cigarette smoke, but the mechanisms responsible for this apparent sex-linkage remain unclear.
The detailed description of the Pald1−/− mouse revealed that the putative phosphatase Pald1 plays a role in the development and function of the lung, and specifically in female pulmonary endothelial cell survival and proliferation. The scientists recommend further studies to address how the lack of Pald1 leads to endothelial cell apoptosis and proliferation, and how that is related to the emphysema phenotype in a sex-specific manner.
Egaña I, Kaito H, Nitzsche A, Becker L, Ballester-Lopez C, Niaudet C, Petkova M, Liu W, Vanlandewijck M, Vernaleken A, Klopstock T, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Rask-Andersen H, Johansson HJ, Lehtiö J, He L, Yildirim AÖ, Hellström M; German Mouse Clinic Consortium. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema. Sci Rep. 2017 Nov 13;7(1):15453. doi: 10.1038/s41598-017-14894-9.