Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

Abstract

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis

“…We next investigated the loss of Pald1 on VEGFR2 signalling in vivo using a global constitutive Pald1 knockout mouse (Wallgard et al , 2012). We examined murine cardiac endothelial cells as an example of microcirculatory endothelial cells responsive to VEGF‐A, moreover, heart endothelial cells express Pald1 and, in contrast to lung endothelial cells, they do not show an overt phenotype in the Pald1 −/− mouse (Wallgard et al , 2012; Egana et al , 2017; Schaum et al , 2018). Accordingly, VEGF‐A was injected into the tail vein of adult mice followed by retrieval and lysis of hearts at specific time points and immunoblotting.…”

“…However, Paladin has been implicated in various cell signalling pathways. A broad phenotypic screen in Pald1 null mice covering all organ systems revealed a specific lung phenotype, i.e., an emphysema‐like lung histology and increased turnover of lung endothelial cells (Egana et al , 2017). In addition, studies on chick embryos support a role for Paladin in neural crest migration (Roffers‐Agarwal et al , 2012).…”

Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia

“…Two aspects might explain why PALD1 had not been previously associated with Hh signaling: i) PALD1 is dispensable for Hh signal transmission in several tissues, as PALD1-deficient IMCD3 cells mount a partial response to Hh (Fig. 8) and Pald1 −/− mice only show a mild phenotype (German Mouse Clinic Consortium et al, 2017). ii) PALD1 is a cell-type specific factor that accumulates in primary cilia of select cell types in response to Hh signal.…”

A big-data approach to understanding metabolic rate and response to obesity in laboratory mice

“…Pald1, phosphatase domain containing paladin 1, is a regulator of angiogenesis and vascular function. Female Pald1 -/exhibit an emphysema-like lung disorder (Egaña et al, 2017). However, cell culture studies have shown Pald1 to have a role in insulin signaling by negatively regulating insulin receptor expression and phosphorylation (Huang et al, 2009).…”