Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

Thomson, Jennifer M.; Singh, Mukti; Eckersley, Alexander; Cain, Stuart A.; Sherratt, Michael J.; Baldock, Clair

doi:10.1016/j.semcdb.2018.07.016

Cited by 108 publications

(97 citation statements)

References 150 publications

(174 reference statements)

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“…Fibrillin microfibrils are evolutionarily ancient extracellular matrix assemblies that form the template for elastic fibres that endow blood vessels, lungs, skin, ligaments and other elastic tissues with essential extensible properties. They also regulate the bioavailability of potent growth factors of the TGFβ and BMP superfamily ( 11 , 12 ). Mutations in Fbn1 most commonly cause Marfan syndrome (MFS) with life-threatening cardiovascular defects, bone overgrowth, joint laxity/contractures and ectopia lentis, caused by elastic fibre defects and/or growth factor dysregulation.…”

Section: Introductionmentioning

confidence: 99%

ADAMTS10-mediated tissue disruption in Weill–Marchesani syndrome

Mularczyk

Singh

Godwin

et al. 2018

Human Molecular Genetics

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Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)10 is an essential factor in fibrillin microfibril function. Mutations in fibrillin-1 or ADAMTS10 cause Weill–Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin. Despite its importance, there is poor understanding of the role of ADAMTS10 and its function in fibrillin microfibril assembly. We have generated an ADAMTS10 WMS mouse model using Clustered Regularly Spaced Interspaced Short Palindromic Repeats and CRISPR associated protein 9 (CRISPR-Cas9) to introduce a truncation mutation seen in WMS patients. Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation. Furthermore, there are abnormalities in the ciliary apparatus of the eye with decreased ciliary processes and abundant fibrillin-2 microfibrils suggesting perturbation of a developmental expression switch. WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis. These results correlated with expression data showing down regulation of Growth differentiation factor (GDF8) and Bone Morphogenetic Protein (BMP) growth factor genes. In addition, the mitochondria in skeletal muscle are larger with irregular shape coupled with increased phospho-p38 mitogen-activated protein kinase (MAPK) suggesting muscle remodelling. Our data indicate that decreased SMAD1/5/8 and increased p38/MAPK signalling are associated with ADAMTS10-induced WMS. This model will allow further studies of the disease mechanism to facilitate the development of therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

ADAMTS10-mediated tissue disruption in Weill–Marchesani syndrome

Mularczyk

Singh

Godwin

et al. 2018

Human Molecular Genetics

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“…Fibrillin microfibrils also play a key role in tissue homeostasis through their interaction with growth factors such as transforming growth factor-β (TGFβ) and bone morphogenetic proteins [2] and through interaction with cell surface receptors such as the integrins [3] , [4] and syndecans [5] . The importance of fibrillin-1 in the function of tissues is further highlighted by fibrillin-1 mutations that cause a number of heritable connective tissue disorders termed fibrillinopathies, such as Marfan syndrome (MFS) [6] and Weill–Marchesani syndrome (WMS) [7] .…”

Section: Introductionmentioning

confidence: 99%

Multiscale Imaging Reveals the Hierarchical Organization of Fibrillin Microfibrils

Godwin

Starborg

Smith

et al. 2018

Journal of Molecular Biology

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Fibrillin microfibrils are evolutionarily ancient, structurally complex extracellular polymers found in mammalian elastic tissues where they endow elastic properties, sequester growth factors and mediate cell signalling; thus, knowledge of their structure and organization is essential for a more complete understanding of cell function and tissue morphogenesis. By combining multiple imaging techniques, we visualize three levels of hierarchical organization of fibrillin structure ranging from micro-scale fiber bundles in the ciliary zonule to nano-scale individual microfibrils. Serial block-face scanning electron microscopy imaging suggests that bundles of zonule fibers are bound together by circumferential wrapping fibers, which is mirrored on a shorter-length scale where individual zonule fibers are interwoven by smaller fibers. Electron tomography shows that microfibril directionality varies from highly aligned and parallel, connecting to the basement membrane, to a meshwork at the zonule fiber periphery, and microfibrils within the zonule are connected by short cross-bridges, potentially formed by fibrillin-binding proteins. Three-dimensional reconstructions of negative-stain electron microscopy images of purified microfibrils confirm that fibrillin microfibrils have hollow tubular structures with defined bead and interbead regions, similar to tissue microfibrils imaged in our tomograms. These microfibrils are highly symmetrical, with an outer ring and interwoven core in the bead and four linear prongs, each accommodating a fibrillin dimer, in the interbead region. Together these data show how a single molecular building block is organized into different levels of hierarchy from microfibrils to tissue structures spanning nano- to macro-length scales. Furthermore, the application of these combined imaging approaches has wide applicability to other tissue systems.

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“…Such complexity presents a technical challenge in unravelling the multiple molecular interactions that FRMs possess. Proteomic analysis such as mass spectrometry has the potential to identify a large number of molecules that colocalize or interact with FRMs (for a review, see Thomson et al, 2019). Although beyond the scope of the current manuscript, future studies could focus on understanding the precise molecular composition of FRMs isolated from individuals of diverse ancestry.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of fibrillin‐rich microfibrils extracted from human skin of diverse ethnicity

et al. 2020

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The dermal elastic fibre network is the primary effector of skin elasticity, enabling it to extend and recoil many times over the lifetime of the individual. Fibrillin‐rich microfibrils (FRMs) constitute integral components of the elastic fibre network, with their distribution showing differential deposition in the papillary dermis across individuals of diverse skin ethnicity. Despite these differential findings in histological presentation, it is not known if skin ethnicity influences FRM ultrastructure. FRMs are evolutionarily highly conserved from jellyfish to man and, regardless of tissue type or species, isolated FRMs have a characteristic ‘beads‐on‐a‐string’ ultrastructural appearance, with an average inter‐bead distance (or periodicity) of 56 nm. Here, skin biopsies were obtained from the photoprotected buttock of healthy volunteers (18‐27 years; African: n = 5; European: n = 5), and FRMs were isolated from the superficial papillary dermis and deeper reticular dermis and imaged by atomic force microscopy. In the reticular dermis, there was no significant difference in FRM ultrastructure between European and African participants. In contrast, in the more superficial papillary dermis, inter‐bead periodicity was significantly larger for FRMs extracted from European participants than from African participants by 2.20 nm (p < .001). We next assessed whether these differences in FRM ultrastructure were present during early postnatal development by characterizing FRMs from full‐thickness neonatal foreskin. Analysis of FRM periodicity identified no significant difference between neonatal cohorts (p = .865). These data suggest that at birth, FRMs are developmentally invariant. However, in adults of diverse skin ethnicity, there is a deviation in ultrastructure for the papillary dermal FRMs that may be acquired during the passage of time from child to adulthood. Understanding the mechanism by which this difference in papillary dermal FRMs arises warrants further study.

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Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

Cited by 108 publications

References 150 publications

ADAMTS10-mediated tissue disruption in Weill–Marchesani syndrome

ADAMTS10-mediated tissue disruption in Weill–Marchesani syndrome

Multiscale Imaging Reveals the Hierarchical Organization of Fibrillin Microfibrils

Heterogeneity of fibrillin‐rich microfibrils extracted from human skin of diverse ethnicity

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