Nonselective Assembly of Fibrillin 1 and Fibrillin 2 in the Rodent Ocular Zonule and in Cultured Cells: Implications for Marfan Syndrome

Abstract

These data suggest that fibrillin 1 assembly and fibrillin 2 assembly share similar mechanisms. Microfibril composition depends substantially on the local levels of fibrillin isoforms and is not highly selective in regard to the isoform. This raises the intriguing possibility that the zonule could be strengthened in MFS by inducing fibrillin 2 expression in ciliary epithelium. The presence of fibrillin 2 in the murine zonule and an intact zonule in Fbn1-knockout mice may limit the utility of rodent models for studying ectopia lentis in MFS.

ADAMTS proteins as modulators of microfibril formation and function

“…In retinal pigment epithelial cells, microfibril assembly was independent of fibronectin, but required syndecan-4, consistent with an observed agonistic effect of heparin–sulfate proteoglycans on microfibril assembly [7,38,39]. However, microfibril assembly in human non-pigmented ciliary epithelial cells was fibronectin-dependent, suggesting that even epithelial cells may have different requirements for fibrillin assembly, presumably owing to diversity of their secretomes [34]. …”

“…Fibrillin isoforms can form microfibrils by homotypic or heterotypic head-to-tail and lateral self-assembly [30–33]. During this process, microfibrils are thought to incorporate fibrillin isoforms indiscriminately depending on their availability at the time of assembly [30,31,34]. FBN2 and FBN3 mRNA expression is prevalent during embryogenesis and FBN1 mRNA is prevalent after birth; therefore, it is generally accepted that the preponderance of FBN1 in adult microfibrils reflects the relatively abundant postnatal expression of this isoform [35–37].…”

“…Furthermore, Adamts10 inactivation in mice did not precisely phenocopy WMS1; although Adamts10 null mice are slightly smaller in size, they lacked specific skeletal and cardiac anomalies and did not develop ectopia lentis (Wang, Kutz, Apte, manuscript in preparation). These inter-species differences are potentially attributable to the absence of FBN3 in mice, to different expression patterns of the ADAMTS proteins in the three species, and the recent observation that the mouse zonule, in contrast to the human zonule, contains both FBN1 and FBN2 [34,76]. It is a distinct possibility that ADAMTS proteins are deployed slightly differently in each species.…”

“…The fibrillins forming the ciliary zonule are synthesized by non-pigmented ciliary epithelial cells located in the ciliary body and the assembled microfibrils insert into the lens capsule [12,34,81]. Several publications have described the composition and arrangement of the zonule, as well as the process of ciliary zonule growth and attachment [12,34,37,76,82–85]. Shi et al showed that Fbn2 expressed by the non-pigmented ciliary epithelium was the dominant embryonic fibrillin isoform in the mouse and that Fbn1 mRNA replaced Fbn2 mRNA around birth [76].…”

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

“…FBN1 binds to each other and forms microfibrils with other proteins, which enables the skin, ligaments, and blood vessels to stretch, and supports more rigid tissues such as nerve, muscle, and lenses of the eyes [12]. Mutations in FBN1 gene can result in Marfan syndrome [13, 14], a disorder that affects the connective tissue supporting the body's joints and organs, and Weill-Marchesani syndrome that causes the eye, heart, and skeletal abnormalities [15]. Growing studies have revealed that FBN1 also functions to regulate organ development and homeostasis [16], integrin α5 assembly [17], and gremlin-1 localization in tumor microenvironment [18].…”