CaltechAUTHORS
  A Caltech Library Service

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

Santos, Rosaysela and Kawauchi, Shimako and Jacobs, Russell E. and Lopez-Burks, Martha E. and Choi, Hojae and Wikenheiser, Jamie and Hallgrimsson, Benedikt and Jamniczky, Heather A. and Fraser, Scott E. and Lander, Arthur D. and Calof, Anne L. (2016) Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS Biology, 14 (9). Art. No. e2000197. ISSN 1544-9173. PMCID PMC5016002. http://resolver.caltech.edu/CaltechAUTHORS:20160919-155707517

[img] PDF - Published Version
Creative Commons Attribution.

19Mb
[img] MS Excel (S1 Data) - Supplemental Material
Creative Commons Attribution.

275Kb
[img] MS Excel (S1 Table) - Supplemental Material
Creative Commons Attribution.

55Kb
[img] MS Excel (S2 Table) - Supplemental Material
Creative Commons Attribution.

137Kb
[img] Image (TIFF) (S1 Fig.) - Supplemental Material
Creative Commons Attribution.

12Mb
[img] Image (TIFF) (S2 Fig.) - Supplemental Material
Creative Commons Attribution.

9Mb
[img] Image (TIFF) (S3 Fig.) - Supplemental Material
Creative Commons Attribution.

9Mb
[img] Image (TIFF) (S4 Fig.) - Supplemental Material
Creative Commons Attribution.

11Mb
[img] Image (TIFF) (S5 Fig.) - Supplemental Material
Creative Commons Attribution.

1200Kb

Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:20160919-155707517

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pbio.2000197DOIArticle
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000197PublisherArticle
http://dx.doi.org/10.1371/journal.pbio.2000197.s001PublisherS1 Data
http://dx.doi.org/10.1371/journal.pbio.2000197.s002PublisherS1 Table
http://dx.doi.org/10.1371/journal.pbio.2000197.s003PublisherS2 Table
http://dx.doi.org/10.1371/journal.pbio.2000197.s004PublisherS1 Fig.
http://dx.doi.org/10.1371/journal.pbio.2000197.s005PublisherS2 Fig.
http://dx.doi.org/10.1371/journal.pbio.2000197.s006PublisherS3 Fig.
http://dx.doi.org/10.1371/journal.pbio.2000197.s007PublisherS4 Fig.
http://dx.doi.org/10.1371/journal.pbio.2000197.s008PublisherS5 Fig.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016002/PubMed CentralArticle
ORCID:
AuthorORCID
Jacobs, Russell E.0000-0002-1382-8486
Fraser, Scott E.0000-0002-5739-4026
Additional Information:© 2016 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 1, 2016; Accepted: August 5, 2016; Published: September 8, 2016. ALC and ADL would like to dedicate this work to the memory of Isabel E. C. Lander and thank the Cornelia de Lange Syndrome (CdLS) Foundation for support and encouragement: UC Irvine is a designated Research Center of Excellence for CdLS. The authors thank Michelle Digman and Jenu Chacko for assistance and advice with confocal microscopy and Sheetal Jotwani for assistance in OPT image analysis. We thank the many dedicated undergraduate researchers who assisted with mouse husbandry and genotyping and Mona Yazdi, Ceyda Yaramanoglu, Tritia Schostak, Harrison DiStefano, Phoebe Yam, David Razo, Salvador Deniz, Qumber Ali, Phoebe Valdes, and Louise A. Villagomez for technical support and assistance with data acquisition for this project. We thank the UC Irvine Transgenic Mouse Facility (TMF) for assistance with IVF experiments. The TMF is a shared resource funded in part by the Chao Family Comprehensive Cancer Center support Grant (P30CA062203) from the National Cancer Institute, and by strategic partnerships with various UCI offices and schools. We also thank the Biological Imaging Center of the Beckman Institute at Caltech; the Canadian Foundation for Innovation, Alberta Innovates, and the University of Calgary; and University of Southern California Translational Imaging Center for support. Funding: National Institute of Child Health and Human Development www.nichd.nih.gov (grant number NICHD P01-HD052860) received by ALC and ADL. National Institute of Biomedical Imaging and Bioengineering https://www.nibib.nih.gov/ (grant number NIBIB R01-EB000993) received by REJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: All relevant data are within the paper and its Supporting Information files. Author Contributions: Contributed equally to this work with: Rosaysela Santos, Shimako Kawauchi Conceptualization: RS SK BH SEF ADL ALC. Formal analysis: RS SK MEL HC ADL. Funding acquisition: ADL ALC. Investigation: RS SK REJ MEL HC JW BH HAJ. Methodology: RS SK REJ MEL JW BH HAJ SEF ADL ALC. Project administration: ADL ALC. Resources: REJ BH SEF ADL ALC. Supervision: ADL ALC. Validation: RS SK MEL ADL ALC. Visualization: RS SK MEL HC HAJ ALC. Writing – original draft: RS SK ADL ALC. Writing – review & editing: ADL ALC. The authors have declared that no competing interests exist.
Funders:
Funding AgencyGrant Number
NIHP01-HD052860
NIHR01-EB000993
PubMed Central ID:PMC5016002
Record Number:CaltechAUTHORS:20160919-155707517
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160919-155707517
Official Citation: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
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70440
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Sep 2016 18:10
Last Modified:28 Sep 2016 18:10

Repository Staff Only: item control page