Podoplanin deficient mice show a RhoA-related hypoplasia of the sinus venosus myocardium including the sinoatrial node

Department of Anatomy and Embryology, Leiden University Medical Center, The Netherlands.
Developmental Dynamics (Impact Factor: 2.38). 01/2009; 238(1):183-93. DOI: 10.1002/dvdy.21819
Source: PubMed


We investigated the role of podoplanin in development of the sinus venosus myocardium comprising the sinoatrial node, dorsal atrial wall, and primary atrial septum as well as the myocardium of the cardinal and pulmonary veins. We analyzed podoplanin wild-type and knockout mouse embryos between embryonic day 9.5-15.5 using immunohistochemical marker podoplanin; sinoatrial-node marker HCN4; myocardial markers MLC-2a, Nkx2.5, as well as Cx43; coelomic marker WT-1; and epithelial-to-mesenchymal transformation markers E-cadherin and RhoA. Three-dimensional reconstructions were made and myocardial morphometry was performed. Podoplanin mutants showed hypoplasia of the sinoatrial node, primary atrial septum, and dorsal atrial wall. Myocardium lining the wall of the cardinal and pulmonary veins was thin and perforated. Impaired myocardial formation is correlated with abnormal epithelial-to-mesenchymal transformation of the coelomic epithelium due to up-regulated E-cadherin and down-regulated RhoA, which are controlled by podoplanin. Our results demonstrate an important role for podoplanin in development of sinus venosus myocardium.

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    • "In this setting, the lack of PDPN leads to a dysregulation of epithelial-mesenchymal transition (EMT), a process that involves the transition of sessile epithelial cells into more motile mesenchymal cells through the downregulation of epithelial markers, such as adhesion molecules like E-cadherin (Thiery, 2002). In PDPN-deficient mice, the epicardium-derived cells responsible for cardiac development show increased levels of E-cadherin and decreased levels of RhoA compared with their WT counterparts, which is indicative of impaired EMT (Mahtab et al., 2008, 2009). While PDPN has been shown to play a role in regulating EMT (Martín-Villar et al., 2006), these studies are the first evidence that PDPN may play a role in physiological instances of EMT in non-transformed cells. "
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    • "These factors are also important for epicardial–myocardial interaction (Perez- Pomares et al., 2002; Merki et al., 2005; Winter and Gittenberger-de Groot, 2007). Recently a role for podoplanin and RhoA in this EMT process has been described (Mahtab et al., 2009). The platelet-derived growth factor (PDGF) family comprises regulators involved in epicardial–myocardial signaling and have been investigated in relation to coronary vascular development (van den Akker et al., 2005, 2008). "
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