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Cardiac neural crest and outflow tract defects in Lrp6 mutant mice
Lanying Song1, Yunhong Li, Kai Wang
1Department of Cell Biology and Human Anatomy, University of California, Davis, School of Medicine, Sacramento, California, USA.
Abstract:
The role of a key Wnt coreceptor Lrp6 during heart development remains unclear. Here we show that ablation of Lrp6 in mice causes conotruncal anomalies including double-outlet right ventricle (DORV), outflow tract (OFT) cushion hypoplasia, and ventricular septal defect (VSD). Cardiac neural crest cells are specifically lost in the dorsal neural tube and caudal pharyngeal arches of the mutant embryos. We also demonstrate that Lrp6 is required for proliferation and survival of cardiac progenitors and for the expression of Isl1 in the secondary heart field. Other known cardiogenic regulators such as Msx1, Msx2, and Fgf8 are also significantly diminished in the mutant pharyngeal arches and/or OFT. Unexpectedly, the myocardium differentiation factors Mef2c and Myocardin are upregulated in the mutant OFT. Our results indicate that Lrp6 is essential for cardiac neural crest and OFT development upstream of multiple important cardiogenic genes in different cardiac lineage cells during early cardiogenesis.
Insights
Low-density lipoprotein receptor-related protein 6 (Lrp6) is essential for heart development. Its absence in mice leads to severe cardiac defects by affecting neural crest cells and key developmental genes.
Area of Science:
- Developmental Biology
- Cardiovascular Research
- Genetics
Background:
- The role of the Wnt signaling pathway coreceptor, Low-density lipoprotein receptor-related protein 6 (Lrp6), in heart development is not fully understood.
- Congenital heart defects, such as conotruncal anomalies, remain a significant clinical challenge, necessitating a deeper understanding of their underlying molecular mechanisms.
Purpose of the Study:
- To investigate the function of Lrp6 in embryonic heart development using a mouse model.
- To elucidate the specific cellular and molecular pathways affected by Lrp6 ablation during cardiogenesis.
Main Methods:
- Generation of Lrp6-deficient mice to study its role in cardiac development.
- Histological analysis of embryonic hearts to identify structural abnormalities.
- Gene expression analysis to assess the impact on cardiogenic regulators and cell populations.
Main Results:
- Lrp6 ablation in mice resulted in conotruncal anomalies, including double-outlet right ventricle (DORV), outflow tract (OFT) cushion hypoplasia, and ventricular septal defect (VSD).
- Loss of Lrp6 led to a specific reduction in cardiac neural crest cells and impaired proliferation and survival of cardiac progenitors.
- Expression of key developmental genes (Isl1, Msx1, Msx2, Fgf8) was diminished, while myocardium differentiation factors (Mef2c, Myocardin) were unexpectedly upregulated in the OFT.
Conclusions:
- Lrp6 is crucial for normal cardiac neural crest cell development and outflow tract formation during early embryogenesis.
- Lrp6 acts upstream of multiple critical cardiogenic genes, influencing various cardiac lineage cells.
- These findings highlight Lrp6 as a key regulator essential for preventing congenital heart defects.
