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Journal of Glaucoma 2014
Review
Topics: Exfoliation Syndrome; Extracellular Matrix Proteins; Fibrillins; Humans; Marfan Syndrome; Microfibrils; Microfilament Proteins; Signal Transduction
PubMed: 25275902
DOI: 10.1097/IJG.0000000000000114 -
Planta Sep 2022TEM and AFM imaging reveal radial orientations and whorl-like arrangements of cellulose microfibrils near the S1/S2 interface. These are explained by wrinkling during...
TEM and AFM imaging reveal radial orientations and whorl-like arrangements of cellulose microfibrils near the S1/S2 interface. These are explained by wrinkling during lamellar cell growth. In the most widely accepted model of the ultrastructure of wood cell walls, the cellulose microfibrils are arranged in helical patterns on concentric layers. However, this model is contradicted by a number of transmission electron microscopy (TEM) studies which reveal a radial component to the microfibril orientations in the cell wall. The idea of a radial component of the microfibril directions is not widely accepted, since it cannot easily be explained within the current understanding of lamellar cell growth. To help clarify the microfibril arrangements in wood cell walls, we have investigated various wood cell wall sections using both transmission electron microscopy and atomic force microscopy, and using various imaging and specimen preparation methods. Our investigations confirm that the microfibrils have a radial component near the interface between the S1 and S2 cell wall layers, and also reveal a whorl-like microfibril arrangement at the S1/S2 interface. These whorl-like structures are consistent with cell wall wrinkling during growth, allowing the radial microfibril component to be reconciled with the established models for lamellar cell growth.
Topics: Cell Wall; Cellulose; Microfibrils; Microscopy, Atomic Force; Wood
PubMed: 36087126
DOI: 10.1007/s00425-022-03976-2 -
Matrix Biology : Journal of the... Sep 2015The microfibril-associated glycoproteins MAGP-1 and MAGP-2 are extracellular matrix proteins that interact with fibrillin to influence microfibril function. The two... (Review)
Review
The microfibril-associated glycoproteins MAGP-1 and MAGP-2 are extracellular matrix proteins that interact with fibrillin to influence microfibril function. The two proteins are related through a 60 amino acid matrix-binding domain but their sequences differ outside of this region. A distinguishing feature of both proteins is their ability to interact with TGFβ family growth factors, Notch and Notch ligands, and multiple elastic fiber proteins. MAGP-2 can also interact with αvβ3 integrins via a RGD sequence that is not found in MAGP-1. Morpholino knockdown of MAGP-1 expression in zebrafish resulted in abnormal vessel wall architecture and altered vascular network formation. In the mouse, MAGP-1 deficiency had little effect on elastic fibers in blood vessels and lung but resulted in numerous unexpected phenotypes including bone abnormalities, hematopoietic changes, increased fat deposition, diabetes, impaired wound repair, and a bleeding diathesis. Inactivation of the gene for MAGP-2 in mice produced a neutropenia yet had minimal effects on bone or adipose homeostasis. Double knockouts had phenotypes characteristic of each individual knockout as well as several additional traits only seen when both genes are inactivated. A common mechanism underlying all of the traits associated with the knockout phenotypes is altered TGFβ signaling. This review summarizes our current understanding of the function of the MAGPs and discusses ideas related to their role in growth factor regulation.
Topics: Alternative Splicing; Amino Acid Sequence; Animals; Bone Development; Contractile Proteins; Extracellular Matrix Proteins; Fibrillins; Gene Expression; Glycoproteins; Hematopoiesis; Humans; Microfibrils; Microfilament Proteins; Molecular Sequence Data; Protein Processing, Post-Translational; RNA Splicing Factors; Wound Healing
PubMed: 25963142
DOI: 10.1016/j.matbio.2015.05.003 -
The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure.Journal of Ocular Pharmacology and... 2014Microfibrils are macromolecular aggregates located in the extracellular matrix of both elastic and nonelastic tissues that have essential functions in formation of... (Review)
Review
Microfibrils are macromolecular aggregates located in the extracellular matrix of both elastic and nonelastic tissues that have essential functions in formation of elastic fibers and control of signaling through the transforming growth factor beta (TGFβ) family of cytokines. Elevation of systemic TGFβ and chronic activation of TGFβ signal transduction are associated with diseases caused by mutations in microfibril-associated genes, including FBN1. A role for microfibrils in glaucoma is suggested by identification of risk alleles in LOXL1 for exfoliation glaucoma and mutations in LTBP2 for primary congenital glaucoma, both of which are microfibril-associated genes. Recent identification of a mutation in another microfibril-associated gene, ADAMTS10, in a dog model of primary open-angle glaucoma led us to form the microfibril hypothesis of glaucoma, which in general states that defective microfibrils may be an underlying cause of glaucoma. Microfibril defects could contribute to glaucoma through alterations in biomechanical properties of tissue and/or through effects on signaling through TGFβ, which is well established to be elevated in the aqueous humor of glaucoma patients. Recent work has shown that diseases caused by microfibril defects are associated with increased concentrations of TGFβ protein and chronic activation of TGFβ-mediated signal transduction. In analogy with other microfibril-related diseases, defective microfibrils could provide a mechanism for the elevation of TGFβ2 in glaucomatous aqueous humor. If glaucoma shares mechanisms with other diseases caused by defective microfibrils, such as Marfan syndrome, therapeutic interventions to inhibit chronic activation of TGFβ signaling used in those diseases may be applied to glaucoma.
Topics: Animals; Disease Models, Animal; Dogs; Extracellular Matrix; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Microfibrils; Mutation; Signal Transduction; Transforming Growth Factor beta
PubMed: 24521159
DOI: 10.1089/jop.2013.0184 -
Matrix Biology : Journal of the... Sep 2015The fibrillins, large extracellular matrix molecules, are polymerized to form "microfibrils." The fibrillin microfibril scaffold is populated by microfibril-associated... (Review)
Review
The fibrillins, large extracellular matrix molecules, are polymerized to form "microfibrils." The fibrillin microfibril scaffold is populated by microfibril-associated proteins and by growth factors, which are likely to be latent. The scaffold, associated proteins, and bound growth factors, together with cellular receptors that can sense the microfibril matrix, constitute the fibrillin microenvironment. Activation of TGFβ signaling is associated with the Marfan syndrome, which is caused by mutations in fibrillin-1. Today we know that mutations in fibrillin-1 cause the Marfan syndrome as well as Weill-Marchesani syndrome (and other acromelic dysplasias) and result in opposite clinical phenotypes: tall or short stature; arachnodactyly or brachydactyly; joint hypermobility or stiff joints; hypomuscularity or hypermuscularity. We also know that these different syndromes are associated with different structural abnormalities in the fibrillin microfibril scaffold and perhaps with specific cellular receptors (mechanosensors). How does the microenvironment, framed by the microfibril scaffold and populated by latent growth factors, work? We must await future investigations for the molecular and cellular mechanisms that will answer this question. However, today we can appreciate the importance of the fibrillin microfibril niche as a contextual environment for growth factor signaling and potentially for mechanosensation.
Topics: Animals; Bone Morphogenetic Proteins; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mechanotransduction, Cellular; Microfibrils; Microfilament Proteins; Transforming Growth Factor beta
PubMed: 25957947
DOI: 10.1016/j.matbio.2015.05.002 -
Experimental Dermatology Jan 2021Supramolecular networks composed of fibrillins (fibrillin-1 and fibrillin-2) and associated ligands form intricate cellular microenvironments which balance skin... (Review)
Review
Supramolecular networks composed of fibrillins (fibrillin-1 and fibrillin-2) and associated ligands form intricate cellular microenvironments which balance skin homoeostasis and direct remodelling. Fibrillins assemble into microfibrils which are not only indispensable for conferring elasticity to the skin, but also control the bioavailability of growth factors targeted to the extracellular matrix architecture. Fibrillin microfibrils (FMF) represent the core scaffolds for elastic fibre formation, and they also decorate the surface of elastic fibres and form independent networks. In normal dermis, elastic fibres are suspended in a three-dimensional basket-like lattice of FMF intersecting basement membranes at the dermal-epidermal junction and thus conferring pliability to the skin. The importance of FMF for skin homoeostasis is illustrated by the clinical features caused by mutations in the human fibrillin genes (FBN1, FBN2), summarized as "fibrillinopathies." In skin, fibrillin mutations result in phenotypes ranging from thick, stiff and fibrotic skin to thin, lax and hyperextensible skin. The most plausible explanation for this spectrum of phenotypic outcomes is that FMF regulate growth factor signalling essential for proper growth and homoeostasis of the skin. Here, we will give an overview about the current understanding of the underlying pathomechanisms leading to fibrillin-dependent fibrosis as well as forms of cutis laxa caused by mutational inactivation of FMF-associated ligands.
Topics: Animals; Bone Diseases, Developmental; Connective Tissue Diseases; Elastic Tissue; Elasticity; Fibrillins; Fibrosis; Homeostasis; Humans; Limb Deformities, Congenital; Microfibrils; Molecular Conformation; Signal Transduction; Skin; Skin Physiological Phenomena; Transforming Growth Factor beta
PubMed: 32920888
DOI: 10.1111/exd.14191 -
Matrix Biology : Journal of the... Nov 2019Fibrillin is a large evolutionarily ancient extracellular glycoprotein that assembles to form beaded microfibrils which are essential components of most extracellular... (Review)
Review
Fibrillin is a large evolutionarily ancient extracellular glycoprotein that assembles to form beaded microfibrils which are essential components of most extracellular matrices. Fibrillin microfibrils have specific biomechanical properties to endow animal tissues with limited elasticity, a fundamental feature of the durable function of large blood vessels, skin and lungs. They also form a template for elastin deposition and provide a platform for microfibril-elastin binding proteins to interact in elastic fibre assembly. In addition to their structural role, fibrillin microfibrils mediate cell signalling via integrin and syndecan receptors, and microfibrils sequester transforming growth factor (TGF)β family growth factors within the matrix to provide a tissue store which is critical for homeostasis and remodelling.
Topics: Animals; Elasticity; Elastin; Extracellular Matrix; Fibrillins; Humans; Microfibrils; Signal Transduction
PubMed: 31226403
DOI: 10.1016/j.matbio.2019.06.006 -
Scientific Reports Jul 2020Microfibril-associated glycoprotein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen-related protein superfamily. MFAP4 is produced by vascular...
Microfibril-associated glycoprotein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen-related protein superfamily. MFAP4 is produced by vascular smooth muscle cells and is highly enriched in the blood vessels of the heart and lung, where it is thought to contribute to the structure and function of elastic fibers. Genetic studies in humans have implicated MFAP4 in the pathogenesis of Smith-Magenis syndrome, in which patients present with multiple congenital abnormalities and mental retardation, as well as in the severe cardiac malformation left-sided congenital heart disease. Comprehensive genetic analysis of the role of MFAP4 orthologues in model organisms during development and tissue homeostasis is however lacking. Here, we demonstrate that zebrafish mfap4 transcripts are detected embryonically, resolving to the macrophage lineage by 24 h post fertilization. mfap4 null mutant zebrafish are unexpectedly viable and fertile, without ostensible phenotypes. However, tail fin amputation assays reveal that mfap4 mutants have reduced numbers of macrophages, with a concomitant increase in neutrophilic granulocytes, although recruitment of both cell types to the site of injury was unaffected. Molecular analyses suggest that loss of Mfap4 alters the balance between myeloid and lymphoid lineages during both primitive and definitive haematopoiesis, which could significantly impact the downstream function of the immune system.
Topics: Animals; Carrier Proteins; Embryonic Development; Extracellular Matrix Proteins; Gene Deletion; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins; Hematopoiesis; Humans; Leukocyte Count; Microfibrils; Phenotype; Zebrafish
PubMed: 32678226
DOI: 10.1038/s41598-020-68792-8 -
Nature Structural & Molecular Biology May 2023Genetic mutations in fibrillin microfibrils cause serious inherited diseases, such as Marfan syndrome and Weill-Marchesani syndrome (WMS). These diseases typically show...
Genetic mutations in fibrillin microfibrils cause serious inherited diseases, such as Marfan syndrome and Weill-Marchesani syndrome (WMS). These diseases typically show major dysregulation of tissue development and growth, particularly in skeletal long bones, but links between the mutations and the diseases are unknown. Here we describe a detailed structural analysis of native fibrillin microfibrils from mammalian tissue by cryogenic electron microscopy. The major bead region showed pseudo eightfold symmetry where the amino and carboxy termini reside. On the basis of this structure, we show that a WMS deletion mutation leads to the induction of a structural rearrangement that blocks interaction with latent TGFβ-binding protein-1 at a remote site. Separate deletion of this binding site resulted in the assembly of shorter fibrillin microfibrils with structural alterations. The integrin αβ-binding site was also mapped onto the microfibril structure. These results establish that in complex extracellular assemblies, such as fibrillin microfibrils, mutations may have long-range structural consequences leading to the disruption of growth factor signaling and the development of disease.
Topics: Animals; Microfibrils; Fibrillins; Extracellular Matrix; Transforming Growth Factor beta; Fibrillin-1; Mutation; Binding Sites; Mammals
PubMed: 37081316
DOI: 10.1038/s41594-023-00950-8 -
Philosophical Transactions of the Royal... Feb 2002Fibrillins form the structural framework of a unique and essential class of extracellular microfibrils that endow dynamic connective tissues with long-range elasticity.... (Review)
Review
Fibrillins form the structural framework of a unique and essential class of extracellular microfibrils that endow dynamic connective tissues with long-range elasticity. Their biological importance is emphasized by the linkage of fibrillin mutations to Marfan syndrome and related connective tissue disorders, which are associated with severe cardiovascular, ocular and skeletal defects. These microfibrils have a complex ultrastructure and it has proved a major challenge both to define their structural organization and to relate it to their biological function. However, new approaches have at last begun to reveal important insights into their molecular assembly, structural organization and biomechanical properties. This paper describes the current understanding of the molecular assembly of fibrillin molecules, the alignment of fibrillin molecules within microfibrils and the unique elastomeric properties of microfibrils.
Topics: Animals; Biomechanical Phenomena; Elasticity; Fibrillins; Humans; Marfan Syndrome; Microfibrils; Microfilament Proteins; Models, Molecular; Protein Structure, Quaternary
PubMed: 11911778
DOI: 10.1098/rstb.2001.1029