Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
- The Francis Crick Institute, United Kingdom
- UCL Institute of Neurology, United Kingdom
- Imperial College London, United Kingdom
Figures
Figure 1
Generation of a mouse mapping panel of partial trisomies for DS phenotypes.
(a) Representation of Hsa21 and the regions of conserved synteny with orthologous regions on Mmu10, Mmu17 and Mmu16 (grey lines), indicating the coordinates of each mouse region. Diagram of Hsa21 …
Figure 2
Dp1Tyb mice recapitulate the CHD seen in DS.
(a) Graph shows the percentage of CHD in Dp1Tyb embryonic hearts at E14.5 compared to wild-type (Wt) littermates; n = 26 Wt and 39 Dp1Tyb embryos. Significant difference to corresponding wild-type …
Figure 3
Genetic dissection of DS-associated CHD.
(a) Representation of Hsa21 showing region of conserved synteny with Mmu16 in grey and the extent of the duplications in Dp9Tyb, Dp2Tyb and Dp3Tyb in black. Graphs show the incidence of CHD in each …
Figure 4
Development of the DMP.
Left panels show a series of 3D four-chamber views of hearts at embryonic stages E11.5, 12.5, 13.5 and 14.5. Middle panels show a close up of the AV junction (frontal plane view corresponds to blue …
Figure 5
Largely normal development of the DMP in Dp1Tyb mice.
(a) 3D reconstruction of control Isl1nLacZ and Isl1nLacZ/Dp1Tyb E11.5 and E12.5 hearts analyzed using dual filter HREM. In the first two columns heart morphology is in grey and LacZ expression is …
Figure 6
Genetic and mechanistic dissection of CHD in mouse models of DS.
(a) Representation of Hsa21 and the conserved region of synteny with the telomeric part of Mmu16 (grey line). Black lines indicate the extent of the duplications in Dp3Tyb and Ts1Rhr strains. …
Videos
Video 1
OA in an E14.5 Dp1Tyb heart.
At the start of the video an image of the whole heart is seen and as it zooms in the frontal erosion of the heart reveals the four-chamber view. The pulmonary valves are seen at 00:05, coming from …
Video 2
DORV in an E14.5 Dp1Tyb heart.
The video starts with an image of the whole heart and frontal erosion reveals that the aorta is communicating with the right ventricle (00:04). The video then zooms in to reveal in more detail how …
Video 3
pVSD in an E14.5 Dp1Tyb heart.
At the start the video shows the whole heart and then erodes frontally to show a pVSD (00:08). The video then erodes slightly further to show the connection of the ventricular septum with the …
Video 4
mVSD in an E14.5 Dp1Tyb heart.
The video shows a whole heart that rotates to view the apex of the ventricles and then erodes transversally revealing the ventricular septum. The mVSD is first seen at 00:08 and the image then zooms …
Video 5
AVSD in an E14.5 Dp1Tyb heart.
The video shows a whole heart that rotates to view the apex of the ventricles and then erodes upwards. The bridging leaflets across the common AV junction can first be seen at 00:05, but they are …
Video 6
AVSD with intact DMP in an E14.5 Dp1Tyb heart.
The video shows the whole heart that initially erodes transversally from the apex to reveal an AVSD (00:03 to 00:07). The heart is then reconstructed and eroded frontally to show a pVSD (00:13). …
Video 7
mVSD in an E14.5 Dp3Tyb heart.
The embryonic heart is eroded upwards from the apex of the ventricles to reveal an mVSD in the inlet portion of the ventricular septum (00:17).
Video 8
AVSD in an E14.5 Dp3Tyb heart.
The heart is first eroded frontally to show a pVSD (00:04). The heart is then reconstructed and eroded from the top of the OFT downwards to reveal an AVSD (00:13 to 00:17).
Tables
Table 1
Yields of wild-type (WT) and mutant mice from the 7 duplication strains.
Table shows the numbers and percentages of wild-type and mutant mice recovered at weaning (~3 weeks old) from each of the 7 duplication strains which were bred by crossing a mutant mouse with a …
| Mouse numbers | Percentages | ||||
|---|---|---|---|---|---|
| Strain | WT | Mutant | WT | Mutant | p-value |
| Dp1Tyb | 427 | 208 | 67.24% | 32.76% | <0.0001 |
| Dp2Tyb | 305 | 253 | 54.66% | 45.34% | ns |
| Dp3Tyb | 223 | 165 | 57.47% | 42.53% | 0.0437 |
| Dp4Tyb | 101 | 78 | 56.42% | 43.58% | ns |
| Dp5Tyb | 99 | 74 | 57.23% | 42.77% | ns |
| Dp6Tyb | 191 | 157 | 54.89% | 45.11% | ns |
| Dp9Tyb | 97 | 91 | 51.60% | 48.40% | ns |
Table 2
Cardiovascular abnormalities in E14.5 embryos.
Table shows the numbers of different cardiac defects found in embryos from the indicated duplication strains and in Wt littermate controls.
| Types of defects | Dp1Tyb | Dp9Tyb | Dp2Tyb | Dp3Tyb | Ts1Rhr | Dp4Tyb | Dp5Tyb | Dp6Tyb | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wt | Dp1Tyb | Wt | Dp9Tyb | Wt | Dp2Tyb | Wt | Dp3Tyb | Wt | Ts1Rhr | Wt | Dp4Tyb | Wt | Dp5Tyb | Wt | Dp6Tyb | |||
| Single defects | Septal defects | ASD | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| pVSD | 3 | 9 | 0 | 1 | 2 | 5 | 2 | 0 | 4 | 1 | 0 | 4 | 1 | 1 | 4 | 1 | ||
| mVSD | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | ||
| OFT defects | OA | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| DORV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| AVSD | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Multiple defects | OFT + VSD | 1 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | |
| pVSD + mVSD | 1 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| VSD + AVSD | 1 | 4 | 0 | 0 | 0 | 0 | 0 | 6 | 1 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | ||
| OFT + VSD + AVSD | 0 | 5 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | ||
| Total number of CHD | 7 | 24 | 1 | 1 | 2 | 9 | 3 | 11 | 5 | 5 | 0 | 4 | 3 | 3 | 6 | 2 | ||
| Embryos analyzed | 26 | 39 | 22 | 17 | 16 | 26 | 26 | 25 | 20 | 21 | 15 | 19 | 11 | 20 | 28 | 19 | ||
| % of CHD | 26.9 | 61.5 | 4.5 | 5.9 | 12.5 | 34.6 | 11.5 | 44.0 | 25.0 | 23.8 | 0 | 21.0 | 27.2 | 15.0 | 21.4 | 10.5 | ||
