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.
Highlights
The PDZ-LIM family of proteins has been shown to regulate diverse biological functions, including bone morphogenesis, cardiac and skeletal muscle development and maintenance, neuronal signaling, and tumor cell growth [1,2]
We provide the first characterization of a global Pdlim7 loss-of-function mouse
As Pdlim7 is widely distributed during embryogenesis, with robust expression in the heart, we hypothesized that a significant number of Pdlim7 mutants die prematurely from a heart defect
Summary
The PDZ-LIM family of proteins has been shown to regulate diverse biological functions, including bone morphogenesis, cardiac and skeletal muscle development and maintenance, neuronal signaling, and tumor cell growth [1,2]. Ten members comprise this protein family: Pdlim, Pdlim, LDB3, LMO7, and LIMK1 and LIMK2, sharing similar domain structures including one PDZ domain and one or more LIM domains. Several PDZ-LIM proteins have been found to function in cardiac and skeletal muscle development and maintenance in zebrafish and mice [3,4,5,6,7,8,9]. Pdlim is the only PDZ-LIM protein described to function in platelets [10], and loss of the protein in mice results in arterial thrombosis [11]
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