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Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves.

Mommersteeg MT, Yeh ML, Parnavelas JG, Andrews WD - Cardiovasc. Res. (2015)

Bottom Line: Loss of Robo1 or both Robo1 and Robo2 resulted in membranous ventricular septum defects at birth, a defect also found in Slit3, but not in Slit2 mutants.Expression of Notch- and downstream Hey and Hes genes was down-regulated in Robo1 mutants, suggesting that reduced Notch signalling in mice lacking Robo might underlie the defects.Luciferase assays confirmed regulation of Notch signalling by Robo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, 21 University Street, London WC1E 6DE, UK m.mommersteeg@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Disrupted Slit-Robo signalling results in membranous ventricular septum defects. (A–L) immunohistochemistry for cardiac Troponin I (cTnI) and DAPI on Robo1+/+ (A, C, and I), Robo1−/− (B, D, and J), Robo2−/− (E), Robo1−/−;Robo2−/− (F), Slit2−/− (G), Slit3+/+ (K) and Slit3−/− (H and L) hearts. The valves and the membranous ventricular septum are visible as green DAPI staining. White arrowhead points to the presence or absence of the membranous ventricular septum (see Table 1 for numbers of embryos analysed). VS, (muscular) ventricular septum. For other abbreviations, see the legend of Figure 1. Scale bars depict 100 µm.
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CVV040F2: Disrupted Slit-Robo signalling results in membranous ventricular septum defects. (A–L) immunohistochemistry for cardiac Troponin I (cTnI) and DAPI on Robo1+/+ (A, C, and I), Robo1−/− (B, D, and J), Robo2−/− (E), Robo1−/−;Robo2−/− (F), Slit2−/− (G), Slit3+/+ (K) and Slit3−/− (H and L) hearts. The valves and the membranous ventricular septum are visible as green DAPI staining. White arrowhead points to the presence or absence of the membranous ventricular septum (see Table 1 for numbers of embryos analysed). VS, (muscular) ventricular septum. For other abbreviations, see the legend of Figure 1. Scale bars depict 100 µm.

Mentions: These expression patterns, combined with the identified roles of Slit-Robo during neural crest migration and adhesion, imply that defective signalling might result in cardiac valve and membranous septum defects. Therefore, we first analysed mice mutant for Robo1 and/or Robo2 receptor for septum defects. At E14.5, we noticed absence of the membranous ventricular septum combined with an overriding aorta in 60% of embryos lacking Robo1 (Figure 2A–D; Table 1), whereas the ventricular septum was closed in all littermate controls at this stage. The membranous ventricular septum closes the communication between the right and left ventricles by fusion of the outflow tract cushions with the atrioventricular cushions and is normally completed at E14.5. Robo2 mutant mice did not show any defects, whereas Robo1;Robo2 double mutants showed a phenotype similar to Robo1 lacking mice, indicating that Robo1 is the main Robo receptor required for the development of the region (Figure 2E and F; Table 1). All double mutants analysed exhibited a septum defect, suggesting an additional role for Robo2, although this difference might be caused by the lower numbers of double mutants analysed. The membranous septum defect was still present in 30% of Robo1 mutants at E18.5 (Figure 2I and J; Table 1), suggesting in one-third of mutants closure is merely delayed as the Mendelian ratio at birth is normal.17Table 1


Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves.

Mommersteeg MT, Yeh ML, Parnavelas JG, Andrews WD - Cardiovasc. Res. (2015)

Disrupted Slit-Robo signalling results in membranous ventricular septum defects. (A–L) immunohistochemistry for cardiac Troponin I (cTnI) and DAPI on Robo1+/+ (A, C, and I), Robo1−/− (B, D, and J), Robo2−/− (E), Robo1−/−;Robo2−/− (F), Slit2−/− (G), Slit3+/+ (K) and Slit3−/− (H and L) hearts. The valves and the membranous ventricular septum are visible as green DAPI staining. White arrowhead points to the presence or absence of the membranous ventricular septum (see Table 1 for numbers of embryos analysed). VS, (muscular) ventricular septum. For other abbreviations, see the legend of Figure 1. Scale bars depict 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362403&req=5

CVV040F2: Disrupted Slit-Robo signalling results in membranous ventricular septum defects. (A–L) immunohistochemistry for cardiac Troponin I (cTnI) and DAPI on Robo1+/+ (A, C, and I), Robo1−/− (B, D, and J), Robo2−/− (E), Robo1−/−;Robo2−/− (F), Slit2−/− (G), Slit3+/+ (K) and Slit3−/− (H and L) hearts. The valves and the membranous ventricular septum are visible as green DAPI staining. White arrowhead points to the presence or absence of the membranous ventricular septum (see Table 1 for numbers of embryos analysed). VS, (muscular) ventricular septum. For other abbreviations, see the legend of Figure 1. Scale bars depict 100 µm.
Mentions: These expression patterns, combined with the identified roles of Slit-Robo during neural crest migration and adhesion, imply that defective signalling might result in cardiac valve and membranous septum defects. Therefore, we first analysed mice mutant for Robo1 and/or Robo2 receptor for septum defects. At E14.5, we noticed absence of the membranous ventricular septum combined with an overriding aorta in 60% of embryos lacking Robo1 (Figure 2A–D; Table 1), whereas the ventricular septum was closed in all littermate controls at this stage. The membranous ventricular septum closes the communication between the right and left ventricles by fusion of the outflow tract cushions with the atrioventricular cushions and is normally completed at E14.5. Robo2 mutant mice did not show any defects, whereas Robo1;Robo2 double mutants showed a phenotype similar to Robo1 lacking mice, indicating that Robo1 is the main Robo receptor required for the development of the region (Figure 2E and F; Table 1). All double mutants analysed exhibited a septum defect, suggesting an additional role for Robo2, although this difference might be caused by the lower numbers of double mutants analysed. The membranous septum defect was still present in 30% of Robo1 mutants at E18.5 (Figure 2I and J; Table 1), suggesting in one-third of mutants closure is merely delayed as the Mendelian ratio at birth is normal.17Table 1

Bottom Line: Loss of Robo1 or both Robo1 and Robo2 resulted in membranous ventricular septum defects at birth, a defect also found in Slit3, but not in Slit2 mutants.Expression of Notch- and downstream Hey and Hes genes was down-regulated in Robo1 mutants, suggesting that reduced Notch signalling in mice lacking Robo might underlie the defects.Luciferase assays confirmed regulation of Notch signalling by Robo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, 21 University Street, London WC1E 6DE, UK m.mommersteeg@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus