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Fibrillins 1 and 2 perform partially overlapping functions during aortic development.
Luca Carta1, Lygia Pereira, Emilio Arteaga-Solis
1Laboratory of Genetics and Organogenesis, Hospital for Special Surgery, the Weill Medical College of Cornell University, New York, New York 10021, USA.
The Journal of Biological Chemistry
|January 13, 2006
Summary
Fibrillin-1 deficiency causes aortic aneurysms and neonatal death in mice. Fibrillins 1 and 2 have overlapping roles in aortic development, with fibrillin-1 crucial for vessel maturation.
Area of Science:
- Connective tissue biology
- Developmental biology
- Vascular biology
Background:
- Fibrillin-rich microfibrils are essential extracellular matrix components providing structural integrity to connective tissues.
- Understanding the specific roles of fibrillins, particularly fibrillin-1 and fibrillin-2, is crucial for elucidating organogenesis and tissue development.
Purpose of the Study:
- To investigate the contribution of fibrillin-rich microfibrils to organogenesis.
- To examine the vascular phenotype of mice lacking fibrillin-1 (Fbn1-/-) and the consequences of combined fibrillin-1 and fibrillin-2 deficiency (Fbn1-/-;Fbn2-/-) on tissue formation.
Main Methods:
- Generation and analysis of novel mouse strains with complete fibrillin-1 deficiency (Fbn1-/-) and combined fibrillin-1/fibrillin-2 deficiency (Fbn1-/-;Fbn2-/-).
- Phenotypic analysis of aortic development, including histology and transcriptional profiling.
- Electron microscopy to visualize microfibril ultrastructure.
Main Results:
- Fbn1-/- mice exhibited aortic aneurysms, impaired pulmonary function, and diaphragmatic collapse, leading to neonatal death.
- Neonatal Fbn1-/- aortas showed disorganized medial layers but normal elastin cross-linking; transcriptional profiling indicated aberrant upregulation of repair-related genes.
- Combined deficiency (Fbn1-/-;Fbn2-/-) resulted in embryonic lethality and a more severe vascular phenotype than Fbn1-/- alone, suggesting partially overlapping functions and specialized roles for fibrillin-2.
Conclusions:
- Fibrillins 1 and 2 play partially overlapping roles in aortic development.
- Fibrillin-2 contributes to early aortic matrix assembly, while fibrillin-1 is essential for neonatal vascular maturation and function.
- Complete absence of fibrillin-1 leads to severe vascular defects and early lethality, highlighting its critical role in maintaining vascular integrity postnatally.