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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    • "the PHF is characterized by the expression of several genes, including Podoplanin (Gittenberger-de Groot et al., 2007; Mahtab et al., 2009), its downstream factor RhoA (Vicente- Steijn et al., 2010), HCN4 (Garcia-Frigola et al., 2003), Shox2 (Blaschke et al., 2007), Tbx5 (Puskaric et al., 2010), and Tbx18 (Christoffels et al., 2006). PHF-derived sinus venosus myocardium is furthermore characterized by the lack of expression of the transcription factor Nkx2.5 (Christoffels et al., 2006; Gittenberger-de Groot et al., 2007). "
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