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Cardiovascular Research 2000 47(2):314-328; doi:10.1016/S0008-6363(00)00098-5
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the Splotch (Sp2H)/Pax3 mouse mutant

Simon J. Conway*, Justin Bundy, Jinwen Chen, Eileen Dickman, Rhonda Rogers and Barbara M. Will

Institute of Molecular Medicine and Genetics and Department of Cell Biology and Anatomy, Medical College of Georgia, 1120 15th Street, CB2803, Augusta, GA 30912-2640, USA

* Corresponding author. Tel.: +1-706-721-8775; fax: +1-706-721-8732 sconway{at}mail.mcg.edu

Objective: Several mouse models of cardiac neural crest cell (NCC)-associated conotruncal heart defects exist, but the specific cellular and molecular defects within cardiac NCC morphogenesis remain largely unknown. Our objective was to investigate the underlying mechanisms resulting in outflow tract defects and why insufficient cardiac NCC reach the heart of the Splotch (Sp2H) mouse mutant embryo. Methods: For this study we used in vitro cell culture techniques, in vivo mouse–chick chimeras, BrdU cell proliferation labeling, TUNEL labeling to visualize apoptosis and the molecular markers AP-2, Wnt-1 and Wnt-3a to characterize NCC morphogenesis in vivo. Results: Expression of the NCC marker AP-2 revealed an extensive reduction in migratory NCC, however the rates of cell proliferation and apoptosis were unaffected, and do not account for the Sp2H NCC-associated heart defects. Further expression analysis revealed that Wnt-1, but not Wnt-3a, is expressed at decreased levels within Sp2H and that the cardiac NCC fail to undergo normal NC stem cell proliferative expansion prior to migration while still in the neural folds. However, when placed into a wild-type matrix or a tissue culture environment, the Sp2H cardiac NCC could migrate normally. Additionally, this reduced population of Sp2H NC stem cells do migrate properly within the Sp2H environment, as observed by neurofilament expression and cardiac innervation. Conclusions:. Taken together, all these data indicate that the Sp2H defect is intrinsic to the NC stem cells themselves and that there is a decrease in the number of pre-migratory cardiac NCC that form. It appears that this decrease in NCC number is the primary defect that ultimately leads to a lack of a cardiac NCC-derived Sp2H outflow tract septum.

KEYWORDS Apoptosis; Congenital defects; Developmental biology


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