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Conditional Creation and Rescue of Nipbl -Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

View Article: PubMed Central - PubMed

ABSTRACT

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form.

No MeSH data available.


Related in: MedlinePlus

NipblFLEX/+ and Nipbl+/- mice develop heart defects at the same high frequency.A, B. Paraffin-sectioned hearts stained with H&E (A) and MRI-scanned hearts (B) show large atrial septal defects (yellow arrowheads) in Nipbl+/- and NipblFLEX/+ mice, but not in wildtype or NipblFlox/+ mice. Scans and histology were performed on fixed tissue from E17.5 embryos. Scale bar = 500 μm. la, left atrium; lv left ventricle; ra, right atrium; rv right ventricle; S, septum. C. Summary table showing incidence of atrial septal defects (ASDs) and ventricular septal defects (VSDs) in hearts of Nipbl+/-, NipblFLEX/+, NipblFlox/+ mice and wildtype littermate embryos at E17.5. Asterisks: p < 0.01 by Chi-square analysis. Data were pooled from analyses of multiple crosses (see S1 Data: Sample Numbers) and progeny are on various backgrounds depending on parental backgrounds: Nipbl+/-, CD-1; NipblFLEX/+, mixed; NipblFlox/+, C57Bl6/J or mixed.
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pbio.2000197.g003: NipblFLEX/+ and Nipbl+/- mice develop heart defects at the same high frequency.A, B. Paraffin-sectioned hearts stained with H&E (A) and MRI-scanned hearts (B) show large atrial septal defects (yellow arrowheads) in Nipbl+/- and NipblFLEX/+ mice, but not in wildtype or NipblFlox/+ mice. Scans and histology were performed on fixed tissue from E17.5 embryos. Scale bar = 500 μm. la, left atrium; lv left ventricle; ra, right atrium; rv right ventricle; S, septum. C. Summary table showing incidence of atrial septal defects (ASDs) and ventricular septal defects (VSDs) in hearts of Nipbl+/-, NipblFLEX/+, NipblFlox/+ mice and wildtype littermate embryos at E17.5. Asterisks: p < 0.01 by Chi-square analysis. Data were pooled from analyses of multiple crosses (see S1 Data: Sample Numbers) and progeny are on various backgrounds depending on parental backgrounds: Nipbl+/-, CD-1; NipblFLEX/+, mixed; NipblFlox/+, C57Bl6/J or mixed.

Mentions: The results are shown in Fig 3. At E17.5, both NipblFLEX/+ and Nipbl+/- hearts display large atrial-septal defects (ASDs) at a similar frequency, about 30% (Fig 3). This number is somewhat smaller than previously reported for Nipbl+/- mice (~50%), because a later time of assessment and more stringent criteria were used here; by these criteria we observed no ASD in wildtype littermates of NipblFLEX/+ and Nipbl+/- mice. We also examined a large number of NipblFlox/+ mice, and found only a single ASD among 48 hearts examined (i.e., 2%, Fig 3C). All ASDs observed in Nipbl-deficient mice were of the ostium secundum type, similar to what is observed in individuals with CdLS, when ASD is seen as an isolated cardiac defect [15]. Ventricular septal defects were not observed in this analysis, nor were arterial stenoses or obvious abnormalities of ventricular wall thickness (S4 Fig). We did note that the hearts of Nipbl-deficient mice, whether NipblFLEX/+ or Nipbl+/-, are noticeably smaller than those of wildtype littermates—to about the same degree that Nipbl-deficient embryos themselves are smaller than wildtypes.


Conditional Creation and Rescue of Nipbl -Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects
NipblFLEX/+ and Nipbl+/- mice develop heart defects at the same high frequency.A, B. Paraffin-sectioned hearts stained with H&E (A) and MRI-scanned hearts (B) show large atrial septal defects (yellow arrowheads) in Nipbl+/- and NipblFLEX/+ mice, but not in wildtype or NipblFlox/+ mice. Scans and histology were performed on fixed tissue from E17.5 embryos. Scale bar = 500 μm. la, left atrium; lv left ventricle; ra, right atrium; rv right ventricle; S, septum. C. Summary table showing incidence of atrial septal defects (ASDs) and ventricular septal defects (VSDs) in hearts of Nipbl+/-, NipblFLEX/+, NipblFlox/+ mice and wildtype littermate embryos at E17.5. Asterisks: p < 0.01 by Chi-square analysis. Data were pooled from analyses of multiple crosses (see S1 Data: Sample Numbers) and progeny are on various backgrounds depending on parental backgrounds: Nipbl+/-, CD-1; NipblFLEX/+, mixed; NipblFlox/+, C57Bl6/J or mixed.
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pbio.2000197.g003: NipblFLEX/+ and Nipbl+/- mice develop heart defects at the same high frequency.A, B. Paraffin-sectioned hearts stained with H&E (A) and MRI-scanned hearts (B) show large atrial septal defects (yellow arrowheads) in Nipbl+/- and NipblFLEX/+ mice, but not in wildtype or NipblFlox/+ mice. Scans and histology were performed on fixed tissue from E17.5 embryos. Scale bar = 500 μm. la, left atrium; lv left ventricle; ra, right atrium; rv right ventricle; S, septum. C. Summary table showing incidence of atrial septal defects (ASDs) and ventricular septal defects (VSDs) in hearts of Nipbl+/-, NipblFLEX/+, NipblFlox/+ mice and wildtype littermate embryos at E17.5. Asterisks: p < 0.01 by Chi-square analysis. Data were pooled from analyses of multiple crosses (see S1 Data: Sample Numbers) and progeny are on various backgrounds depending on parental backgrounds: Nipbl+/-, CD-1; NipblFLEX/+, mixed; NipblFlox/+, C57Bl6/J or mixed.
Mentions: The results are shown in Fig 3. At E17.5, both NipblFLEX/+ and Nipbl+/- hearts display large atrial-septal defects (ASDs) at a similar frequency, about 30% (Fig 3). This number is somewhat smaller than previously reported for Nipbl+/- mice (~50%), because a later time of assessment and more stringent criteria were used here; by these criteria we observed no ASD in wildtype littermates of NipblFLEX/+ and Nipbl+/- mice. We also examined a large number of NipblFlox/+ mice, and found only a single ASD among 48 hearts examined (i.e., 2%, Fig 3C). All ASDs observed in Nipbl-deficient mice were of the ostium secundum type, similar to what is observed in individuals with CdLS, when ASD is seen as an isolated cardiac defect [15]. Ventricular septal defects were not observed in this analysis, nor were arterial stenoses or obvious abnormalities of ventricular wall thickness (S4 Fig). We did note that the hearts of Nipbl-deficient mice, whether NipblFLEX/+ or Nipbl+/-, are noticeably smaller than those of wildtype littermates—to about the same degree that Nipbl-deficient embryos themselves are smaller than wildtypes.

View Article: PubMed Central - PubMed

ABSTRACT

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form.

No MeSH data available.


Related in: MedlinePlus