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Laser Capture Microdissection of Mouse Embryonic Cartilage and Bone for Gene Expression Analysis
Published on: December 18, 2019
Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment
Jason R Cook1, Silvia Smaldone, Carmine Cozzolino
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
Loss-of-function experiments in mice have yielded invaluable mechanistic insights into the pathogenesis of Marfan syndrome (MFS) and implicitly, into the multiple roles fibrillin-1 microfibrils play in the developing and adult organism. Unfortunately, neonatal death from aortic complications of mice lacking fibrillin-1 (Fbn1(-/-) mice) has limited the scope of these studies. Here, we report the creation of a conditional mutant allele (Fbn1(fneo) ) that contains loxP sites bordering exon1 of Fbn1 and an frt-flanked neo expression cassette downstream of it. Fbn1(fneo/+) mice were crossed with FLPeR mice and the resulting Fbn1(Lox/+) progeny were crossed with Fbn1(+/-) ;CMV-Cre mice to generate Fbn1(CMV-/-) mice, which were found to phenocopy the vascular abnormalities of Fbn1(-/-) mice. Furthermore, mating Fbn1(Lox/+) mice with Prx1-Cre or Osx-Cre mice revealed an unappreciated role of fibrillin-1 microfibrils in restricting osteoprogenitor cell recruitment. Fbn1(Lox/+) mice are, therefore, an informative genetic resource to further dissect MFS pathogenesis and the role of extracellular fibrillin-1 assemblies in organ development and homeostasis.
Insights
Researchers developed a new mouse model to study Marfan syndrome (MFS). This model overcomes early death issues, enabling deeper investigation into fibrillin-1
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Cardiovascular Research
Background:
- Loss-of-function studies in mice are crucial for understanding Marfan syndrome (MFS) pathogenesis.
- Neonatal mortality in fibrillin-1 deficient mice (Fbn1(-/-)) limits research scope.
- Fibrillin-1 microfibrils play vital roles in organism development and homeostasis.
Purpose of the Study:
- To create a conditional mouse model for studying Marfan syndrome (MFS).
- To overcome limitations of early lethality in Fbn1(-/-) mice.
- To investigate the role of fibrillin-1 in vascular and skeletal development.
Main Methods:
- Generated a conditional mutant allele (Fbn1(fneo)) with loxP sites flanking exon1.
- Utilized FLPeR and CMV-Cre mice for targeted gene deletion.
- Crossed Fbn1(Lox/+) mice with Prx1-Cre or Osx-Cre mice to assess tissue-specific roles.
Main Results:
- Generated Fbn1(CMV-/-) mice that phenocopy vascular abnormalities of Fbn1(-/-) mice.
- Identified an unappreciated role of fibrillin-1 in restricting osteoprogenitor cell recruitment.
- Demonstrated the utility of Fbn1(Lox/+) mice for dissecting MFS pathogenesis.
Conclusions:
- The conditional Fbn1(fneo) allele provides a valuable tool for MFS research.
- Fibrillin-1 microfibrils are critical for vascular integrity and osteoprogenitor cell regulation.
- This genetic resource facilitates further study of extracellular matrix roles in development and homeostasis.
