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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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Loss of Ftm leads to shorter cardiac cilia.(A, B) Immunofluorescence on transverse heart sections at E11.5. Cilia are stained in green by acetylated α-tubulin and cell nuclei in blue by DAPI. Scale bars (in white) represent a length of 2 µm. Ftm is localised at cardiac cilia (A), but is absent from Ftm-negative cilia (B). (C) Comparison of wild-type and Ftm-deficient ciliary length in ventricles and atria (n = 50 cilia, respectively). Ftm-negative cilia are significantly shorter in both ventricles (p = 3.41E−12) and atria (p = 2.79E−06).
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pone-0057545-g003: Loss of Ftm leads to shorter cardiac cilia.(A, B) Immunofluorescence on transverse heart sections at E11.5. Cilia are stained in green by acetylated α-tubulin and cell nuclei in blue by DAPI. Scale bars (in white) represent a length of 2 µm. Ftm is localised at cardiac cilia (A), but is absent from Ftm-negative cilia (B). (C) Comparison of wild-type and Ftm-deficient ciliary length in ventricles and atria (n = 50 cilia, respectively). Ftm-negative cilia are significantly shorter in both ventricles (p = 3.41E−12) and atria (p = 2.79E−06).

Mentions: We previously showed that Ftm is present at the base of cilia in cell culture [20] and others observed Ftm at cilia of murine eyes and brains [48], but nothing is known about the localisation of Ftm at cardiac cilia. Consequently, we looked for Ftm in wild-type hearts. The staining of Ftm and acetylated α-tubulin (indicative for the ciliary axoneme) in combination with the partly overlapping staining of Ftm and γ-tubulin (basal body marker) reveals that Ftm is located at the base of atrial and ventricular cilia (Figure 3A; Figure S4A). Meanwhile, Ftm is completely missing in Ftm-negative embryos (Figure 3B; Figure S4B). Since the loss of Ftm in some cilia leads to a change in ciliary morphology (e.g. nodal cilia; [20]) and since the alteration of ciliary length leads to ciliary dysfunction [27],[55]–[57], we analysed the length of Ftm-homozygous mutant, cardiac cilia at E11.5. Cilia of Ftm-deficient ventricles and atria are clearly shorter than in the wild-type (Figure 3C) arguing for a possible ciliary dysfunction in those hearts. Thus, Ftm is necessary for regulating the length of cardiac cilia.


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

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

Loss of Ftm leads to shorter cardiac cilia.(A, B) Immunofluorescence on transverse heart sections at E11.5. Cilia are stained in green by acetylated α-tubulin and cell nuclei in blue by DAPI. Scale bars (in white) represent a length of 2 µm. Ftm is localised at cardiac cilia (A), but is absent from Ftm-negative cilia (B). (C) Comparison of wild-type and Ftm-deficient ciliary length in ventricles and atria (n = 50 cilia, respectively). Ftm-negative cilia are significantly shorter in both ventricles (p = 3.41E−12) and atria (p = 2.79E−06).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057545-g003: Loss of Ftm leads to shorter cardiac cilia.(A, B) Immunofluorescence on transverse heart sections at E11.5. Cilia are stained in green by acetylated α-tubulin and cell nuclei in blue by DAPI. Scale bars (in white) represent a length of 2 µm. Ftm is localised at cardiac cilia (A), but is absent from Ftm-negative cilia (B). (C) Comparison of wild-type and Ftm-deficient ciliary length in ventricles and atria (n = 50 cilia, respectively). Ftm-negative cilia are significantly shorter in both ventricles (p = 3.41E−12) and atria (p = 2.79E−06).
Mentions: We previously showed that Ftm is present at the base of cilia in cell culture [20] and others observed Ftm at cilia of murine eyes and brains [48], but nothing is known about the localisation of Ftm at cardiac cilia. Consequently, we looked for Ftm in wild-type hearts. The staining of Ftm and acetylated α-tubulin (indicative for the ciliary axoneme) in combination with the partly overlapping staining of Ftm and γ-tubulin (basal body marker) reveals that Ftm is located at the base of atrial and ventricular cilia (Figure 3A; Figure S4A). Meanwhile, Ftm is completely missing in Ftm-negative embryos (Figure 3B; Figure S4B). Since the loss of Ftm in some cilia leads to a change in ciliary morphology (e.g. nodal cilia; [20]) and since the alteration of ciliary length leads to ciliary dysfunction [27],[55]–[57], we analysed the length of Ftm-homozygous mutant, cardiac cilia at E11.5. Cilia of Ftm-deficient ventricles and atria are clearly shorter than in the wild-type (Figure 3C) arguing for a possible ciliary dysfunction in those hearts. Thus, Ftm is necessary for regulating the length of cardiac cilia.

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