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Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome

Nature Genetics volume 33, pages 407–411 (2003)Cite this article

Abstract

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1–3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome4. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-β attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

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Figure 1: Lung histopathology and morphometry of mice deficient in fibrillin-1.
Figure 2: Cell differentiation and elastin deposition in the lungs of mice deficient in fibrillin-1.
Figure 3: Active TGF-β expression and signaling in lung tissue of mice deficient in fibrillin-1.
Figure 4: Neutralizing antibody to TGF-β rescues lung maturation in mice deficient in fibrillin-1.
Figure 5: Mice deficient in fibrillin-1 have preserved lung cell proliferation but greater apoptosis.
Figure 6: Lung phenotype of wild-type (+/+) and Fbn1mgR/mgR (−/−) mice.

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Acknowledgements

We thank J. Gauthier for providing reagents, D. Valle for helpful comments about the manuscript, M. Barcellos-Hoffs for advice about the use of TGF-β antibodies, M. Dellanoy for help with confocal imaging and members of H.C.D.'s laboratory for their support and advice. This work was supported by Robert Wood Johnson Foundation (to E.R.N.), Howard Hughes Medical Institute (to H.C.D.), US National Institutes of Health grants (to E.R.N., H.C.D. and F.R.), the Michael Murray fund from the National Marfan Foundation (to H.C.D.), Smilow Foundation (to H.C.D.) and Dr. Amy and James Elster Research Fund (to F.R.).

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Enid R. Neptune

  2. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Enid R. Neptune, Pamela A. Frischmeyer, Dan E. Arking, Loretha Myers & Harry C. Dietz

  3. Department of Safety Assessment, Dupont Phamaceuticals Company, Newark, 19714, Delaware, USA

    Tracie E. Bunton

  4. Hospital for Special Surgery, New York, 10021, New York, USA

    Barbara Gayraud & Francesco Ramirez

  5. Shriners Hospital, Portland, 97201, Oregon, USA

    Lynn Y. Sakai

  6. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Harry C. Dietz

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  1. Enid R. Neptune
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Correspondence to Harry C. Dietz.

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Neptune, E., Frischmeyer, P., Arking, D. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33, 407–411 (2003). https://doi.org/10.1038/ng1116

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