Extracellular Microfibrils in Vertebrate Development and Disease Processes*

Fibrillins are large cysteine-rich glycoproteins that are evolutionarily conserved from scyphozoans to mammals. Fibrillin assemblies (microfibrils) serve two key physiological functions: the function of a structural support that imparts tissue integrity and the function of a regulator of signaling events that instruct cellular performance (1, 2). The importance of microfibrils in organ formation and tissue homeostasis was originally underscored by the finding that mutations of human fibrillin-1 and fibrillin-2 are responsible for the pleiotropic manifestations of MFS2 (OMIM 154700) and congenital contractural arachnodactyly (OMIM 121050), respectively (3). Fibrillins display a common modular structure that consists predominantly of cbEGF domains interspersed with TB/8-Cys modules (Fig. 1) (1, 2, 4). TB/8-Cys modules are unique to fibrillins and LTBPs. Fibrillins polymerize into microfibrils in which individual molecules are organized in a head-to-tail arrangement and interact laterally; furthermore, microfibrils associate or interact with additional proteins, such as elastin in elastic fibers (Fig. 2) (1, 2, 4, 5). Fibrillins also control the bioavailability of endogenous (local) TGFβ and BMP ligands by targeting the respective complexes to the ECM (Fig. 1) (1–3). FIGURE 1. Schematic representation of prototypical fibrillin and LTBPs (not in scale). Sites of interactions between fibrillin and TGFβ and BMP complexes are shown. For a detailed description of the structural features of fibrillins and LTBPs, see Hubmacher ... FIGURE 2. Diagram highlighting the main steps in microfibril biogenesis. They include the polymerization of fibrillins in a head-to-tail organization (step a) that is visualized by electron microscopy as multiple strings with regularly spaced beads (step b). ... This article focuses on the instructive function of fibrillin-rich microfibrils in organ development and tissue homeostasis. A number of excellent reviews are available that describe in greater detail the structural and biosynthetic aspects of fibrillin assemblies (2, 4, 5).

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