Fibrillin‐rich microfibrils: Structural determinants of morphogenetic and homeostatic events

Abstract

Fibrillin-rich microfibrils are specialized extracellular matrix assemblies that endow connective tissues with mechanical stability and elastic properties, and that participate in the regulation of organ formation, growth and homeostasis. Their physiological importance is underscored by the complex spectrum of clinical manifestations associated with mutations of fibrillin-1 and fibrillin-2 in Marfan syndrome (MFS) and congenital contractural arachnodactyly, respectively. Early evidence suggested that fibrillin-1 mutations in MFS lead to loss of tissue integrity by perturbing microfibril assembly and function. Recent studies in genetically targeted mice have however revealed that fibrillin-1 and fibrillin-2 mutations perturb signaling events mediated by TGF-b superfamily members. As such, these studies have established a new biological paradigm whereby fibrillin-rich microfibrils are structural networks that specify the local concentration and timely release of signaling molecules during morphogenesis and tissue remodeling. This review summarizes our current understanding of the role of fibrillin-rich microfibrils in development and disease, as well as exciting new applications in the clinical management of MFS and related connective tissue disorders.

Pravastatin Reduces Marfan Aortic Dilation

“…Fibrillin-1 is a component of microfibrils that provide a connection between elastin fibers and vascular smooth muscle cells to provide signaling for homeostasis within the aortic wall. 13 Structural homology between the fibrillins and latent TGF-␤-binding proteins suggests an additional role for fibrillin-1 in targeting TGF-␤ to the extracellular matrix and keeping it in an inactive state. A deficiency of fibrillin-1 therefore would lead to excessive TGF-␤ signaling.…”

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

“…Functional binding studies identified distinct sites on MAGP-1 for binding to tropoelastin and fibrillin-1 and -2, consistent with it being a bridging molecule that binds tropoelastin onto the microfibril during elastin assembly (24). Recent studies with fibrillin mutant mice, however, suggest that microfibrils play little role in the initial stages of elastin assembly and, instead, contribute to tissue development and function through interactions with growth factors (25,26).…”

Fibrillin Assembly Requires Fibronectin

“…High-molecular-weight, multiprotein assemblies called microfibrils are the functional units of fibrillins, which serve as a scaffold for the biogenesis of elastic fibers, confer structural integrity to individual organ systems, regulate growth factor signaling of TGF-␤-bone morphogenic protein (BMP) superfamily members and provide limited elasticity to tissues (Kielty et al, 2002;Charbonneau et al, 2004;Ramirez and Dietz, 2007). Extracted microfibrils from cell culture or tissues display a typical bead-on-a-string ultrastructure, having a 50 -55-nm periodicity when analyzed by electron microscopy after rotary shadowing Kielty et al, 1991).…”

“…Fibrillins are mainly composed of tandem arrays of calcium-binding epidermal growth factor-like domains interspersed with TGF-␤-binding protein domains (TB/8-Cys) and hybrid domains Hubmacher et al, 2006). Mutations in fibrillins give rise to the so-called fibrillinopathies, which include Marfan syndrome and autosomal dominant Weill-Marchesani syndrome, both caused by mutations in fibrillin-1, and Beal's syndrome, caused by mutations in fibrillin-2 (Robinson et al, 2006).High-molecular-weight, multiprotein assemblies called microfibrils are the functional units of fibrillins, which serve as a scaffold for the biogenesis of elastic fibers, confer structural integrity to individual organ systems, regulate growth factor signaling of TGF-␤-bone morphogenic protein (BMP) superfamily members and provide limited elasticity to tissues (Kielty et al, 2002;Charbonneau et al, 2004;Ramirez and Dietz, 2007). Extracted microfibrils from cell culture or tissues display a typical bead-on-a-string ultrastructure, having a 50 -55-nm periodicity when analyzed by electron microscopy after rotary shadowing Kielty et al, 1991).…”