N-cadherin is required for neural crest remodeling of the cardiac outflow tract.
Cardiac neural crest cells undergo extensive cell rearrangements during the formation of the aorticopulmonary septum in the outflow tract. However, the morphogenetic mechanisms involved in this fundamental process remain poorly understood. To determine the function of the Ca2+-dependent cell adhesion molecule, N-cadherin, in murine neural crest, we applied the Cre/loxP system and created mouse embryos genetically mosaic for N-cadherin. Specifically, deletion of N-cadherin in neural crest cells led to embryonic lethality with distinct cardiovascular defects. Neural crest cell migration and homing to the cardiac outflow tract niche were unaffected by loss of N-cadherin. However, N-cadherin-deficient neural crest cells were unable to undergo the normal morphogenetic changes associated with outflow tract remodeling, resulting in persistent truncus arteriosus in the majority of mutant embryos. Other mutant embryos initiated aorticopulmonary septum formation; however, the neural crest cells were unable to elongate and align properly along the midline and remained rounded with limited contact with their neighbors. Interestingly, rotation of the outflow tract was incomplete in these mutants suggesting that alignment of the channels is dependent on N-cadherin-generated cytoskeletal forces. A second cardiac phenotype was observed where loss of N-cadherin in the epicardium led to disruption of heterotypic cell interactions between the epicardium and myocardium resulting in a thinned ventricular myocardium. Thus, we conclude that in addition to its role in myocardial cell adhesion, N-cadherin is required for neural crest cell rearrangements critical for patterning of the cardiac outflow tract and in the maintenance of epicardial-myocardial cell interactions.
Luo
Yang
Y
Center for Research on Reproduction and Women's Health, University of Pennsylvania, 1355 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
High
Frances A
FA
Epstein
Jonathan A
JA
Radice
Glenn L
GL
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D005318:Fetal Heart / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism
D015820:Cadherins