Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects
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Published on: January 20, 2013
Jikui Wang1, Andre Nagy, Jonas Larsson
1Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. jikwang@chla.usc.edu
Background:
Congenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. While TGF-beta-superfamily signaling has been strongly implicated in neural crest cell development, the detailed molecular signaling mechanisms in vivo are still poorly understood.
Results:
We deleted the TGF-beta type I receptor Alk5 specifically in the mouse neural crest cell lineage. Failure in signaling via ALK5 leads to severe cardiovascular and pharyngeal defects, including inappropriate remodeling of pharyngeal arch arteries, abnormal aortic sac development, failure in pharyngeal organ migration and persistent truncus arteriosus. While ALK5 is not required for neural crest cell migration, our results demonstrate that it plays an important role in the survival of post-migratory cardiac neural crest cells.
Conclusion:
Our results demonstrate that ALK5-mediated signaling in neural crest cells plays an essential cell-autonomous role in the pharyngeal and cardiac outflow tract development.
Insights
Transforming growth factor-beta (TGF-β) signaling via ALK5 is crucial for cardiac neural crest cell survival and development. This study reveals ALK5
Area of Science:
- Developmental biology
- Cardiovascular research
- Stem cell biology
Background:
- Congenital cardiovascular diseases are common birth defects.
- Neural crest cell development is critical for heart formation.
- TGF-β superfamily signaling is implicated but poorly understood in vivo.
Purpose of the Study:
- To investigate the role of TGF-β type I receptor ALK5 in neural crest cell development.
- To elucidate the in vivo molecular mechanisms of TGF-β signaling in cardiac development.
Main Methods:
- Conditional deletion of the Alk5 gene in mouse neural crest lineage.
- Analysis of cardiovascular and pharyngeal defects in knockout mice.
Main Results:
- Alk5 deletion in neural crest cells caused severe cardiovascular and pharyngeal defects.
- ALK5 is essential for the survival of post-migratory cardiac neural crest cells.
- ALK5 is not required for neural crest cell migration itself.
Conclusions:
- ALK5-mediated signaling is cell-autonomously required for pharyngeal and cardiac outflow tract development.
- This study highlights a critical role for ALK5 in ensuring cardiac neural crest cell viability.
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