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Neural crest is involved in development of abnormal myocardial function
S J Conway1, R E Godt, C J Hatcher
1Developmental Biology Program, Institute of Molecular Medicine and Genetics, Augusta, GA 30912-2640, USA.
Journal of Molecular and Cellular Cardiology
|November 5, 1997
Summary
A Pax3 mutation causes persistent truncus arteriosus and embryonic death in mice due to impaired excitation-contraction coupling. This cardiac neural crest defect reduces calcium currents, leading to heart failure.
Area of Science:
- Developmental Biology
- Cardiovascular Physiology
- Genetics
Background:
- Splotch (Sp2H) allele, a Pax3 mutation, leads to persistent truncus arteriosus (PTA) in 85% of homozygous embryos, causing embryonic lethality.
- The cardiac neural crest plays a crucial role in heart development, but its precise contribution to congenital heart defects remains incompletely understood.
Purpose of the Study:
- To investigate the cause of embryonic lethality in Sp2H/Sp2H mice with PTA.
- To determine the functional consequences of the Pax3 mutation on cardiac mechanics and excitation-contraction coupling.
Main Methods:
- In situ digital video imaging microscopy of embryonic hearts at 13.5 days post coitum.
- Assessment of contractile force in detergent-skinned ventricular muscle strips.
- Analysis of calcium transients and currents in isolated ventricular myocytes using patch clamp techniques.
Main Results:
- Sp2H/Sp2H embryos with PTA exhibited significantly reduced cardiac function and impaired excitation-contraction (EC) coupling.
- Maximum contractile force and myosin content were normal, ruling out contractile apparatus dysfunction.
- A 3.2-fold reduction in calcium current magnitude was observed in defective hearts, identified as the cause of impaired EC coupling.
Conclusions:
- Neural crest abnormalities resulting from the Pax3 mutation lead to impaired EC coupling and depressed myocardial function, causing in utero cardiac failure.
- Impaired EC coupling is secondary to the Pax3 mutation and is specifically associated with PTA.
- This study provides the first demonstration of impaired EC coupling in a genetic embryonic model of cardiac structural defects, highlighting the neural crest's role in myocardial function.