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Heart defect genes both inside and outside the heart

Congenital heart defects (CHDs) are a leading cause of birth defect-related deaths. How genetic alterations cause such defects is complicated by the fact that CHD's many critical genes are unknown. Those that are known often contribute only small increases in CHD risk.


In new research published in the open access journal PLOS Biology, scientists report that genes in Congenital Heart Defects (CHDs) are more complex than previously realized. Overall risk for CHDs are a combination of gene effects both inside and outside of the heart itself.

Normal heart formation depends on interactions of multiple types of cells in precise timing and placement throughout development to build the heart's intricate structures. To figure out how these interactions can go awry, the team of Anne Calof, Arthur Lander and their colleagues studied atrial septal defects (ASDs) as a common type of heart defect in a mouse model of Cornelia de Lange Syndrome (CdLS).

Most cases of Cornelia de Lange Syndrome are caused by mutations that inactivate a single copy of the gene Nipbl, which directs expression of hundreds of other genes in tissues throughout the body. Just as people with Cornelia de Lange Syndrome have a high incidence of heart defects, 30 percent of mice that harbor Nipbl like mutations exhibit ASDs.

Using genetically modified mouse models, researchers used a novel technology to selectively introduce and remove Nipbl mutations in various tissues during embryonic development. Unexpectedly, they found no Nipbl deficiency in any single tissue — including tissue forming the heart — could singlehandedly account for the development of atrial septal defects.


The development of heart defects was determined by interactions between heart-forming tissues and the rest of the body. In fact in certain situations, Nipbl deficiency in some tissues seemed to protect against the development of atrial septal defects.


In a Primer article that accompanies this research, Bruce Gelb, MD, from the Icahn School of Medicine at Mount Sinai, explains and writes that these "mind-bending results provide novel insights into incomplete penetrance and oligogenic effects underlying CHD."  He adds the novel observations "add further complexity to the way in which we need to think about CHD pathogenesis".


"Our results lead us to hypothesize that heart defects such as ASDs occur when the heart does not grow quickly enough to meet the demands of the developing body. In other words, that heart size and body size must be coordinated for the heart to develop without defects. To our knowledge, this is the first genetic demonstration that major risk factors for heart defects are likely to lie outside of the heart itself."

Anne L. Calof PhD, Professor of Anatomy & Neurobiology, Department of Developmental and Cell Biology; Center for Complex Biological Systems; Department of Anatomy and Neurobiology, University of California, Irvine, California, USA

"When a single gene change causes a birth defect, we often assume that it's because one thing goes wrong in one cell type. The big difference in our studies may have to do with the fact that Nipbl controls a large number of other genes.

"Given that most human CHDs are now thought to be caused by gene variants acting in combination, what we learned from Nipbl-deficient mice may actually be more typical of the way most CHDs arise."


Arthur D. Lander PhD, the Donald Bren Professor of Center for Complex Biological Systems, University of California, Irvine, California; Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, USA


Calof and Lander, in collaboration with researchers at Children's Hospital of Philadelphia, helped identify the causative gene for Cornelia de Lange Syndrome in 2004 in the paper: Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.

Their discovery of the impact of the Nipbl gene, has led to the development of tools for molecular diagnosis of CdLS and spawned a large body of biomedical research on CdLS and related syndromes. As part of this effort, Calof, Lander and their UCI colleague Thomas Schilling, Professor of Developmental & Cell Biology, have developed animal models of CdLS that are being used to find ways to prevent and/or treat this disorder.

Their work has been recognized by the CdLS Foundation, and UCI has been designated a Center of Research Excellence in Cornelia de Lange Syndrome.

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.

Author Summary
Congenital heart defects, the most common birth defect, are thought mainly to arise through interactions among multiple genes. We studied atrial septal defects (a common type of heart defect) in a mouse model of Cornelia de Lange Syndrome, in which loss of one copy of the Nipbl gene produces frequent developmental abnormalities. By causing subtle dysregulation of the expression of many hundreds of genes, Nipbl haploinsufficiency serves as a model for the polygenic origins of common birth defects. We used an improved genetic technology to separately create or rescue deficiency for Nipbl within the major cardiogenic tissue lineages (lineages that contribute to or control the morphogenesis of the developing heart). Unexpectedly, we found that risk for developing atrial septal defects could not be mapped to any single one of these cardiogenic lineages, but rather was determined by non-additive interactions between these lineages and the rest of the body. Intriguingly, being Nipbl-deficient in the rest of the body reduced the risk conferred by being Nipbl-deficient in either of two distinct cardiogenic lineages. We hypothesize that this effect is driven by developmental coupling between body size and heart size, with defects arising when progenitor cells cannot be provided fast enough to meet the requirements imposed on the heart by other growing tissues. To our knowledge, this is the first genetic demonstration that major risk factors for heart defects are likely to lie outside of the heart itself.

In your coverage please use this URL to provide access to the freely available article in PLOS Biology:
(Research Article) http://dx.doi.org/10.1371/journal.pbio.2000197
(Primer) http://dx.doi.org/10.1371/journal.pbio.2000494

Citation
(RA) Santos R, Kawauchi S, Jacobs RE, Lopez-Burks ME, Choi H, Wikenheiser J, et al. (2016) Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS Biol 14(9): e2000197. doi:10.1371/journal.pbio.2000197
(P) Gelb BD (2016) The Hole and the Whole: Lessons from Manipulation of Nipbl Deficiency. PLoS Biol 14(9): e2000494. doi:10.1371/journal.pbio.2000494
Image Caption: Optical projection tomography of an E10.5 Nipbl+/- mouse embryo shows, on the left, a three-dimensional reconstruction of the embryo with heart highlighted in red; on the right is an optical section through the heart showing an abnormally small right ventricle.

Funding
(RA) National Institute of Child Health and Human Development http://www.nichd.nih.gov (grant number NICHD P01-HD052860).(Received by ALC and ADL). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; National Institute of Biomedical Imaging and Bioengineering https://www.nibib.nih.gov/ (grant number NIBIB R01-EB000993).(Received by REJ). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
(P) NHLBI (grant number HL098123). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests
(RA) The authors have declared that no competing interests exist.
(P) The authors have declared that no competing interests exist.

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Sep 28, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



(LEFT) Mouse embryo 3D reconstruction with heart highlighted in red.
(RIGHT) Heart showing abnormally small (ARROW) right ventricle.
Image Credit: Benedikt Hallgrimsson/University of Calgary.


 


 

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