title: Loss of the cytoskeletal protein Pdlim7 predisposes mice to heart defects and hemostatic dysfunction.
abstract: The actin-associated protein Pdlim7 is essential for heart and fin development in zebrafish; however, the expression and function of this PDZ-LIM family member in the mammal has remained unclear. Here, we show that Pdlim7 predominantly localizes to actin-rich structures in mice including the heart, vascular smooth muscle, and platelets. To test the requirement for Pdlim7 in mammalian development and function, we analyzed a mouse strain with global genetic inactivation of Pdlim7. We demonstrate that Pdlim7 loss-of-function leads to significant postnatal mortality. Inactivation of Pdlim7 does not disrupt cardiac development, but causes mild cardiac dysfunction in adult mice. Adult Pdlim7(-/-) mice displayed increased mitral and tricuspid valve annulus to body weight ratios. These structural aberrations in Pdlim7(-/-) mice were supported by three-dimensional reconstructions of adult cardiac valves, which revealed increased surface area to volume ratios for the mitral and tricuspid valve leaflets. Unexpectedly, we found that loss of Pdlim7 triggers systemic venous and arterial thrombosis, leading to significant mortality shortly after birth in Pdlim7(+/-) (11/60) and Pdlim7(-/-) (19/35) mice. In line with a prothrombotic phenotype, adult Pdlim7(-/-) mice exhibit dramatically decreased tail bleed times compared to controls. These findings reveal a novel and unexpected function for Pdlim7 in maintaining proper hemostasis in neonatal and adult mice.
authors.affiliation: Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America ; Ann and Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago, Illinois, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Krcmery
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gupta
authors.forename: Rudyard W
authors.initials: RW
authors.lastname: Sadleir
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Ahrens
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Christine
authors.initials: C
authors.lastname: Kamide
authors.forename: Philip
authors.initials: P
authors.lastname: Fitchev
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Simon
mesh_terms: D000199:Actins / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000818:Animals; D001772:Blood Cell Count; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D006321:Heart / Q000196:embryology / Q000503:physiopathology*; D006330:Heart Defects, Congenital / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D006351:Heart Valves / Q000002:abnormalities / Q000473:pathology; D006487:Hemostasis; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D013927:Thrombosis / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D014886:Weaning
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484381:Pdlim7 protein, mouse