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Updated: Jul 29, 2025
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
TGFβ-2 haploinsufficiency causes early death in mice with Marfan syndrome
Nalani Sachan1, Colin K L Phoon2, Lior Zilberberg1
1Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, 10016, USA.
Abstract:
To assess the contribution of individual TGF-β isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-β1, 2, or 3 heterozygous null mutation. The loss of TGF-β2, and only TGF-β2, resulted in 80% of the double mutant animals dying earlier, by postnatal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-β2 in the postnatal development of the heart, aorta and lungs.
Insights
Loss of TGF-β2 in Marfan syndrome mice significantly shortens lifespan and alters heart, aorta, and lung development. This highlights TGF-β2
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Research
- Developmental Biology
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, primarily caused by mutations in the fibrillin-1 gene.
- Aortopathy, characterized by aortic root dilation and potential rupture, is a major cause of mortality in MFS.
- Transforming growth factor-beta (TGF-β) signaling is implicated in MFS pathogenesis, but the roles of individual TGF-β isoforms are not fully understood.
Purpose of the Study:
- To investigate the specific contribution of each TGF-β isoform (TGF-β1, TGF-β2, and TGF-β3) to the development of aortopathy and associated phenotypes in a mouse model of Marfan syndrome.
Main Methods:
- Generation of double mutant mice combining a hypomorphic mutation in fibrillin-1 with heterozygous null mutations in TGF-β1, TGF-β2, or TGF-β3.
- Quantification of survival rates and detailed phenotypic analysis of the double mutant mice, focusing on cardiovascular and pulmonary structures.
Main Results:
- The loss of TGF-β2, but not TGF-β1 or TGF-β3, significantly increased mortality in fibrillin-1 mutant mice, with 80% dying by postnatal day 20.
- Deaths in TGF-β2 deficient double mutants were not due to thoracic aortic rupture but were associated with hyperplastic aortic valve leaflets, aortic regurgitation, aortic root enlargement, increased heart weight, and impaired lung alveolar septation.
Conclusions:
- TGF-β2 plays a critical, previously unrecognized role in the postnatal development of the heart, aorta, and lungs in the context of fibrillin-1 deficiency.
- Targeting TGF-β2 may offer a therapeutic strategy for mitigating specific cardiovascular and pulmonary complications in Marfan syndrome.
