Targetting of the gene encoding fibrillin–1 recapitulates the vascular aspect of Marfan syndrome

Pereira, Lygia V.; Ανδρικόπουλος, Κωνσταντίνος; Tian, Jenny; Lee, Sui Ying; Keene, Douglas R.; Ono, Robert N.; Reinhardt, Dieter P.; Sakai, Lynn Y.; Biery, Nancy Jensen; Bunton, Tracie E.; Dietz, Harry C.; Ramirez, Francesco

doi:10.1038/ng1097-218

Cited by 358 publications

(309 citation statements)

References 22 publications

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“…However, interpreting these experiments is complicated by functional redundancy exhibited by these molecules, which has its basis in the ability of fibrillins to form either homotypic or heterotypic microfibrils (Lin et al, 2002;Charbonneau et al, 2003). For example, gene targeting of either Fbn 1 or 2 in mouse (and mice lack Fbn 3; Corson et al, 2004) is compatible with normal development and both microfibrils and elastic fibers are assembled in either case, consistent with the observation that both fibrillins are co-expressed through much of development (Pereira et al, 1997;Arteaga-Solis et al, 2001). However, in regions where co-expression is not observed, phenotypes are uncovered in these knockout mice (Arteaga-Solis et al, 2001).…”

Section: Roles For Fibrillin In Embryosmentioning

confidence: 61%

Xenopus fibrillin is expressed in the organizer and is the earliest component of matrix at the developing notochord‐somite boundary

Skoglund

Dzamba

Coffman

et al. 2006

Developmental Dynamics

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We identify a Xenopus fibrillin homolog (XF), and show that its earliest developmental expression is in presumptive dorsal mesoderm at gastrulation, and that XF expression is regulated by mesoderm-inducing factors in animal cap assays. XF protein is also first detected in presumptive mesoderm, but is concentrated specifically into extracellular-matrix structures that begin to develop de novo by mid-gastrulation at both of the bilateral presumptive notochord-somite boundaries. Later in embryogenesis, XF protein is localized to the extracellular matrix at tissue boundaries, where it is found surrounding the notochord, the somites, and the neural tube, as well as under the epidermis. This pattern of protein deposition combines to give the appearance of an "embryonic skeleton," suggesting that one role for XF is to serve as a mechanical element in the embryo prior to bone deposition.

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Section: Roles For Fibrillin In Embryosmentioning

confidence: 61%

Xenopus fibrillin is expressed in the organizer and is the earliest component of matrix at the developing notochord‐somite boundary

Skoglund

Dzamba

Coffman

et al. 2006

Developmental Dynamics

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“…Support for this hypothesis is seen in mouse models of MFS. Three strains of transgenic mice, each harboring a different type of Fbn1 mutation, displayed several MFS features with variable severity Pereira et al 1997Pereira et al , 1999. Increased TGFb activity was observed in at least four organs (lung, mitral valve, aortic and dural tissues), possibly as a result of excess free LLC due to inadequate stabilization within the ECM, as previously hypothesized (Habashi et al 2006;Jones et al 2005;Neptune et al 2003;Ng et al 2004;Rifkin 2005).…”

Section: Tgfb Signaling and Connective Tissue Disordersmentioning

confidence: 66%

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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“…B, Proteins from wild-type (WT) control (pa/pa) mouse or tight skin 1 (tsk/pa) mouse fibroblast supernatants were precipitated and analyzed as in A and C. See Figure 2 for other definitions. a similar role for fibrillin based on the vascular pathology of mice harboring a targeted homozygous mutation in fibrillin that leads to an internally deleted protein (47). Homozygous mutant mice develop Marfan's syndrome-like features and die perinatally due to vascular complications.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

Kissin¹,

Lemaire²,

Korn³

et al. 2002

Arthritis & Rheumatism

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Objective. Fibrillin, an extracellular matrix protein implicated in dermal fibrosis, is increased in the reticular dermis of systemic sclerosis (SSc) skin. We undertook this study to investigate the hypothesis that transforming growth factor ␤ (TGF␤) or other cytokines regulate fibrillin matrix formation by normal and SSc fibroblasts. We further investigated the mechanism of TGF␤-induced fibrillin fibrillogenesis and its relationship to myofibroblasts.Methods. Fibrillin and fibronectin matrix deposition and ␣-smooth muscle actin expression by fibroblast cultures from normal and SSc skin treated with TGF␤ or other cytokines were analyzed by immunofluorescence. Supernatant and extracellular matrix from normal and SSc fibroblasts treated with or without TGF␤ were evaluated by Western blot and Northern blot for fibrillin protein and messenger RNA (mRNA) expression, respectively.Results. Immunofluorescence demonstrated increased fibrillin matrix formation by normal and scleroderma fibroblasts after TGF␤ treatment. Other cytokines, including tumor necrosis factor ␣, interleukin-1␤ (IL-1␤), IL-4, granulocyte-macrophage colonystimulating factor, and platelet-derived growth factor, did not affect fibrillin fibrillogenesis. Fibrillin matrix formed in proximity to myofibroblasts and independently of up-regulation of fibronectin matrix or cell number. Western blot analysis of extracellular matrix confirmed increased fibrillin after TGF␤ stimulation of normal or scleroderma fibroblasts. However, TGF␤ did not alter the expression of either soluble fibrillin protein or fibrillin mRNA.Conclusion. Our data show that TGF␤ induces fibrillin protein incorporation into the extracellular matrix without affecting fibrillin gene expression or protein synthesis, suggesting that fibrillin matrix assembly is regulated extracellularly. TGF␤ might increase fibrillin matrix by activating myofibroblasts. Such TGF␤-mediated effects could account for the increased fibrillin matrix observed in SSc skin.

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Targetting of the gene encoding fibrillin–1 recapitulates the vascular aspect of Marfan syndrome

Cited by 358 publications

References 22 publications

Xenopus fibrillin is expressed in the organizer and is the earliest component of matrix at the developing notochord‐somite boundary

Xenopus fibrillin is expressed in the organizer and is the earliest component of matrix at the developing notochord‐somite boundary

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

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