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.

Download full-text


Available from: Lambertus J Wisse, Oct 14, 2015

Click to see the full-text of:

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

8.76 MB

See full-text
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer.
    Frontiers in Immunology 09/2012; 3:283. DOI:10.3389/fimmu.2012.00283
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.
    Developmental Dynamics 11/2011; 240(11):2561-77. DOI:10.1002/dvdy.22762 · 2.38 Impact Factor
  • Source
    • "Mesothelial cells are derived from coelomic epithelium via mesenchymal-epithelial transition (MET), explaining the co-expression of cytokeratin and vimentin.13,14 This co-expression pattern is retained in the malignant mesothelioma. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deciduoid mesothelioma is a rare variant of the epithelioid histotype spectrum, resembling decidua of gravid uterus. It is found in the peritoneum of young women, but also in the pleura of elderly people. Histotype plasticity from epithelioid to sarcomatoid mesothelioma may be considered as epithelial-mesenchymal transition (EMT). A full autopsy was performed and mesothelioma infiltrates were analysed by immunohistochemistry. The metastasis of an epithelioid pleural mesothelioma to a hyperplastic polyp of the stomach is presented in this autopsy case. Deciduoid morphology increased during tumour progression and metastasis. The increase in eosinophilic cytoplasm correlated with the upregulation of the intermediate filament vimentin. High expression of vimentin was found in both central and superficial periglandular regions of the polyp. High vimentin expression also can occur in epithelioid rather than sarcomatoid differentiation. Thus, although vimentin is considered to be the major EMT marker, additional pathways must regulate its expression.
    Rare tumors 10/2011; 3(4):e52. DOI:10.4081/rt.2011.e52
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.