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The ciliary protein Ftm is required for ventricular wall and septal development.

Gerhardt C, Lier JM, Kuschel S, Rüther U - PLoS ONE (2013)

Bottom Line: Despite several studies of the molecular mechanisms involved in ventricular septum (VS) development, very little is known about VS-forming signaling.Since Ftm is a ciliary protein, we investigated presence and function of cilia in murine hearts.Primary cilia could be detected at distinct positions in atria and ventricles at embryonic days (E) 10.5-12.5.

View Article: PubMed Central - PubMed

Affiliation: Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Düsseldorf, Germany.

ABSTRACT
Ventricular septal defects (VSDs) are the most common congenital heart defects in humans. Despite several studies of the molecular mechanisms involved in ventricular septum (VS) development, very little is known about VS-forming signaling. We observed perimembranous and muscular VSDs in Fantom (Ftm)-negative mice. Since Ftm is a ciliary protein, we investigated presence and function of cilia in murine hearts. Primary cilia could be detected at distinct positions in atria and ventricles at embryonic days (E) 10.5-12.5. The loss of Ftm leads to shortened cilia and a reduced proliferation in distinct atrial and ventricular ciliary regions at E11.5. Consequently, wall thickness is diminished in these areas. We suggest that ventricular proliferation is regulated by cilia-mediated Sonic hedgehog (Shh) and platelet-derived growth factor receptor α (Pdgfrα) signaling. Accordingly, we propose that primary cilia govern the cardiac proliferation which is essential for proper atrial and ventricular wall development and hence for the fully outgrowth of the VS. Thus, our study suggests ciliopathy as a cause of VSDs.

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Model of VS development.Myocardial (violett), endocardial (orange) and most likely trabecular cilia (turquoise) regulate proliferation at distinct cardiac regions. In the ventricles, the cell proliferation in these regions results in wall thickness control, trabecular formation and a push of cells toward the base of the muscular ventricular septum (indicated by pink arrows). ECC cilia (yellow) seem to be different from the other cardiac cilia, since they do not regulate ECC proliferation. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; muVS, muscular ventricular septum.
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pone-0057545-g009: Model of VS development.Myocardial (violett), endocardial (orange) and most likely trabecular cilia (turquoise) regulate proliferation at distinct cardiac regions. In the ventricles, the cell proliferation in these regions results in wall thickness control, trabecular formation and a push of cells toward the base of the muscular ventricular septum (indicated by pink arrows). ECC cilia (yellow) seem to be different from the other cardiac cilia, since they do not regulate ECC proliferation. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; muVS, muscular ventricular septum.

Mentions: Assuming that cardiac cilia regulate proliferation, our data allow us to propose a model for how the VS is generated. Ventricular cells at distinct positions assemble monocilia on their surface. These cardiac cilia contain components of Shh and Pdgfrα signaling most likely permitting them to mediate those signals. Thus, target genes of those signaling pathways are activated in cilia-possessing, ventricular cells. Interestingly, in ventricular cilia Pdgfrα signaling acts downstream of Shh signaling. In the end, the mediation of these different signals by cardiac cilia stimulates the cells to proliferate and this proliferation leads to a push of cells to the base of the muscular VS (Figure 9). Thus, in Ftm-negative ventricles the wall thickness of non-ciliary regions near the base of the muscular VS is significantly thinner (Figure 4D) due to the numeral reduction of cells which are pushed towards the base of the muscular VS. Both, the pushed cells and the trabecular formations shape the muscular VS which on its part grows to a certain point and then interacts molecularly with the ECCs. In turn, the ECCs start to shape the membranous VS which then grows towards the muscular VS. When they meet, they fuse and the development of the VS is finished. So finally, the muscular VS consists of cells which descend from the left and right ventricular walls and from the trabecular formations. Thus, our model supports the idea of muscular septal formation as a product of a passive process based on proliferation of cells at distinct regions in the left and right ventricles.


The ciliary protein Ftm is required for ventricular wall and septal development.

Gerhardt C, Lier JM, Kuschel S, Rüther U - PLoS ONE (2013)

Model of VS development.Myocardial (violett), endocardial (orange) and most likely trabecular cilia (turquoise) regulate proliferation at distinct cardiac regions. In the ventricles, the cell proliferation in these regions results in wall thickness control, trabecular formation and a push of cells toward the base of the muscular ventricular septum (indicated by pink arrows). ECC cilia (yellow) seem to be different from the other cardiac cilia, since they do not regulate ECC proliferation. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; muVS, muscular ventricular septum.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585374&req=5

pone-0057545-g009: Model of VS development.Myocardial (violett), endocardial (orange) and most likely trabecular cilia (turquoise) regulate proliferation at distinct cardiac regions. In the ventricles, the cell proliferation in these regions results in wall thickness control, trabecular formation and a push of cells toward the base of the muscular ventricular septum (indicated by pink arrows). ECC cilia (yellow) seem to be different from the other cardiac cilia, since they do not regulate ECC proliferation. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; muVS, muscular ventricular septum.
Mentions: Assuming that cardiac cilia regulate proliferation, our data allow us to propose a model for how the VS is generated. Ventricular cells at distinct positions assemble monocilia on their surface. These cardiac cilia contain components of Shh and Pdgfrα signaling most likely permitting them to mediate those signals. Thus, target genes of those signaling pathways are activated in cilia-possessing, ventricular cells. Interestingly, in ventricular cilia Pdgfrα signaling acts downstream of Shh signaling. In the end, the mediation of these different signals by cardiac cilia stimulates the cells to proliferate and this proliferation leads to a push of cells to the base of the muscular VS (Figure 9). Thus, in Ftm-negative ventricles the wall thickness of non-ciliary regions near the base of the muscular VS is significantly thinner (Figure 4D) due to the numeral reduction of cells which are pushed towards the base of the muscular VS. Both, the pushed cells and the trabecular formations shape the muscular VS which on its part grows to a certain point and then interacts molecularly with the ECCs. In turn, the ECCs start to shape the membranous VS which then grows towards the muscular VS. When they meet, they fuse and the development of the VS is finished. So finally, the muscular VS consists of cells which descend from the left and right ventricular walls and from the trabecular formations. Thus, our model supports the idea of muscular septal formation as a product of a passive process based on proliferation of cells at distinct regions in the left and right ventricles.

Bottom Line: Despite several studies of the molecular mechanisms involved in ventricular septum (VS) development, very little is known about VS-forming signaling.Since Ftm is a ciliary protein, we investigated presence and function of cilia in murine hearts.Primary cilia could be detected at distinct positions in atria and ventricles at embryonic days (E) 10.5-12.5.

View Article: PubMed Central - PubMed

Affiliation: Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Düsseldorf, Germany.

ABSTRACT
Ventricular septal defects (VSDs) are the most common congenital heart defects in humans. Despite several studies of the molecular mechanisms involved in ventricular septum (VS) development, very little is known about VS-forming signaling. We observed perimembranous and muscular VSDs in Fantom (Ftm)-negative mice. Since Ftm is a ciliary protein, we investigated presence and function of cilia in murine hearts. Primary cilia could be detected at distinct positions in atria and ventricles at embryonic days (E) 10.5-12.5. The loss of Ftm leads to shortened cilia and a reduced proliferation in distinct atrial and ventricular ciliary regions at E11.5. Consequently, wall thickness is diminished in these areas. We suggest that ventricular proliferation is regulated by cilia-mediated Sonic hedgehog (Shh) and platelet-derived growth factor receptor α (Pdgfrα) signaling. Accordingly, we propose that primary cilia govern the cardiac proliferation which is essential for proper atrial and ventricular wall development and hence for the fully outgrowth of the VS. Thus, our study suggests ciliopathy as a cause of VSDs.

Show MeSH
Related in: MedlinePlus