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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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Related in: MedlinePlus

Ftm-deficient murine embryos show perimembranous and muscular ventricular septal defects.(A, B) Hematoxylin and Eosin stainings at E14.5 on transverse heart sections. (A) In wild-type mouse embryos, the ventricular septum consists of a muscular part (muVS) and a membranous part (meVS). (B) In Ftm−/− embryos, the muscular VS displays a shorter and thinner shape and the membranous VS is missing (indicated by the asterisk) representing a perimembranous ventricular septal defect. (C) While in Ftm+/+ (n = 23) and Ftm+/− mice (n = 21) the heart develops normally, 33% of Ftm−/− mice (n = 27) show perimembranous ventricular septal defects. This statistics is based on investigations of mice at E13.5, E14.5, E15.5, E16.5 and E17.5. (D) Ftm+/+ mouse embryos (n = 23) do not suffer from muscular ventricular septal defects. 81.5% of all analyzed Ftm−/− embryos (n = 27) display muscular ventricular septal defects. Embryos at E13.5, E14.5, E15.5, E16.5 and E17.5 were examined in this context. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; meVS, membranous ventricular septum; muVS, muscular ventricular septum; AS, atrial septum.
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pone-0057545-g001: Ftm-deficient murine embryos show perimembranous and muscular ventricular septal defects.(A, B) Hematoxylin and Eosin stainings at E14.5 on transverse heart sections. (A) In wild-type mouse embryos, the ventricular septum consists of a muscular part (muVS) and a membranous part (meVS). (B) In Ftm−/− embryos, the muscular VS displays a shorter and thinner shape and the membranous VS is missing (indicated by the asterisk) representing a perimembranous ventricular septal defect. (C) While in Ftm+/+ (n = 23) and Ftm+/− mice (n = 21) the heart develops normally, 33% of Ftm−/− mice (n = 27) show perimembranous ventricular septal defects. This statistics is based on investigations of mice at E13.5, E14.5, E15.5, E16.5 and E17.5. (D) Ftm+/+ mouse embryos (n = 23) do not suffer from muscular ventricular septal defects. 81.5% of all analyzed Ftm−/− embryos (n = 27) display muscular ventricular septal defects. Embryos at E13.5, E14.5, E15.5, E16.5 and E17.5 were examined in this context. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; meVS, membranous ventricular septum; muVS, muscular ventricular septum; AS, atrial septum.

Mentions: 33% of all analysed Ftm-homozygous mutant embryos (9 of 27 embryos) show perimembranous VSDs marked by the combination of a significantly thinner muscular part of the VS and the absence of the membranous part of the VS (Figure 1B, C), while none of the Ftm-heterozygous mutants exhibits an abnormal heart phenotype (Figure 1C). We measured the length and thickness of ventricular and atrial septa in Ftm+/+ and Ftm−/− hearts, respectively, and found out that the atrial septum (AS) displays no differences between the wild-type and Ftm-negative state (data not shown). Furthermore, we did not observe any morphological AS abnormalities. In contrast to the atria, Ftm-deficient ventricles display defects, but the length measurements do not reflect a significant alteration at different embryonic days (Figure S1A, D, G, J, M). This is due to the fact that the frequency of perimembranous VSDs in the absence of Ftm is too low during embryonic development (Figure S1B, E, H, K, N). At E13.5 40% of all analyzed Ftm−/− mouse embryos (2 of 5) suffer from perimembranous VSDs, at E14.5 50% (3 of 6), at E15.5 67% (2 of 3), at E16.5 0% (none of 4) and at E17.5 22% (2 of 9). Compared to the length measurements, the width of Ftm-negative VS is significantly reduced (Figure S1A, D, G, J, M) characterizing a muscular VSD. 81, 5% of all analyzed Ftm−/− embryos (22 of 27 embryos) suffer from muscular VSDs (Figure 1D). The reduction of muscular VS width is significant at all analyzed embryonic days from E13.5 to E17.5 (Figure S1A, D, G, J, M), since the frequency of muscular VSDs is high in all embryonic stages (Figure S1C, F, I, L, O). At E13.5 muscular VSDs can be observed in 80% of all analysed Ftm-negative embryos (4 of 5), at E14.5 in 83% (5 of 6), at E15.5 in 100% (3 of 3), at E16.5 in 50% (2 of 4) and at E17.5 in 89% (8 of 9). These data indicate that the muscular VS defect takes place in a high frequency even if the loss of the membranous VS occurs only in a minority of all Ftm−/− embryos leading to the conclusion that muscular VS development is severly disturbed in most Ftm-deficient embryos.


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

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

Ftm-deficient murine embryos show perimembranous and muscular ventricular septal defects.(A, B) Hematoxylin and Eosin stainings at E14.5 on transverse heart sections. (A) In wild-type mouse embryos, the ventricular septum consists of a muscular part (muVS) and a membranous part (meVS). (B) In Ftm−/− embryos, the muscular VS displays a shorter and thinner shape and the membranous VS is missing (indicated by the asterisk) representing a perimembranous ventricular septal defect. (C) While in Ftm+/+ (n = 23) and Ftm+/− mice (n = 21) the heart develops normally, 33% of Ftm−/− mice (n = 27) show perimembranous ventricular septal defects. This statistics is based on investigations of mice at E13.5, E14.5, E15.5, E16.5 and E17.5. (D) Ftm+/+ mouse embryos (n = 23) do not suffer from muscular ventricular septal defects. 81.5% of all analyzed Ftm−/− embryos (n = 27) display muscular ventricular septal defects. Embryos at E13.5, E14.5, E15.5, E16.5 and E17.5 were examined in this context. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; meVS, membranous ventricular septum; muVS, muscular ventricular septum; AS, atrial septum.
© Copyright Policy
Related In: Results  -  Collection

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pone-0057545-g001: Ftm-deficient murine embryos show perimembranous and muscular ventricular septal defects.(A, B) Hematoxylin and Eosin stainings at E14.5 on transverse heart sections. (A) In wild-type mouse embryos, the ventricular septum consists of a muscular part (muVS) and a membranous part (meVS). (B) In Ftm−/− embryos, the muscular VS displays a shorter and thinner shape and the membranous VS is missing (indicated by the asterisk) representing a perimembranous ventricular septal defect. (C) While in Ftm+/+ (n = 23) and Ftm+/− mice (n = 21) the heart develops normally, 33% of Ftm−/− mice (n = 27) show perimembranous ventricular septal defects. This statistics is based on investigations of mice at E13.5, E14.5, E15.5, E16.5 and E17.5. (D) Ftm+/+ mouse embryos (n = 23) do not suffer from muscular ventricular septal defects. 81.5% of all analyzed Ftm−/− embryos (n = 27) display muscular ventricular septal defects. Embryos at E13.5, E14.5, E15.5, E16.5 and E17.5 were examined in this context. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; meVS, membranous ventricular septum; muVS, muscular ventricular septum; AS, atrial septum.
Mentions: 33% of all analysed Ftm-homozygous mutant embryos (9 of 27 embryos) show perimembranous VSDs marked by the combination of a significantly thinner muscular part of the VS and the absence of the membranous part of the VS (Figure 1B, C), while none of the Ftm-heterozygous mutants exhibits an abnormal heart phenotype (Figure 1C). We measured the length and thickness of ventricular and atrial septa in Ftm+/+ and Ftm−/− hearts, respectively, and found out that the atrial septum (AS) displays no differences between the wild-type and Ftm-negative state (data not shown). Furthermore, we did not observe any morphological AS abnormalities. In contrast to the atria, Ftm-deficient ventricles display defects, but the length measurements do not reflect a significant alteration at different embryonic days (Figure S1A, D, G, J, M). This is due to the fact that the frequency of perimembranous VSDs in the absence of Ftm is too low during embryonic development (Figure S1B, E, H, K, N). At E13.5 40% of all analyzed Ftm−/− mouse embryos (2 of 5) suffer from perimembranous VSDs, at E14.5 50% (3 of 6), at E15.5 67% (2 of 3), at E16.5 0% (none of 4) and at E17.5 22% (2 of 9). Compared to the length measurements, the width of Ftm-negative VS is significantly reduced (Figure S1A, D, G, J, M) characterizing a muscular VSD. 81, 5% of all analyzed Ftm−/− embryos (22 of 27 embryos) suffer from muscular VSDs (Figure 1D). The reduction of muscular VS width is significant at all analyzed embryonic days from E13.5 to E17.5 (Figure S1A, D, G, J, M), since the frequency of muscular VSDs is high in all embryonic stages (Figure S1C, F, I, L, O). At E13.5 muscular VSDs can be observed in 80% of all analysed Ftm-negative embryos (4 of 5), at E14.5 in 83% (5 of 6), at E15.5 in 100% (3 of 3), at E16.5 in 50% (2 of 4) and at E17.5 in 89% (8 of 9). These data indicate that the muscular VS defect takes place in a high frequency even if the loss of the membranous VS occurs only in a minority of all Ftm−/− embryos leading to the conclusion that muscular VS development is severly disturbed in most Ftm-deficient embryos.

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