Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects.
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.
Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
Rosaysela
R
Santos
Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
Shimako
S
Kawauchi
Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, United States of America.
Russell E
RE
Jacobs
Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
Martha E
ME
Lopez-Burks
Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
Hojae
H
Choi
Department of Anatomy and Neurobiology, University of California, Irvine, California, United States of America.
Jamie
J
Wikenheiser
Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada.
Benedikt
B
Hallgrimsson
Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada.
Heather A
HA
Jamniczky
Departments of Biology and Bioengineering, University of Southern California, Los Angeles, California, United States of America.
Scott E
SE
Fraser
Center for Complex Biological Systems, University of California, Irvine, California, United States of America.|Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, United States of America.
Arthur D
AD
Lander
Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, California, United States of America.|Department of Anatomy and Neurobiology, University of California, Irvine, California, United States of America.
Anne L
AL
Calof
D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006321:Heart / Q000196:embryology; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009928:Organ Specificity; D019683:Penetrance; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D000072576:Homeobox Protein Nkx-2.5; C546088:Nipbl protein, mouse; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors