Are Fibrillin‐Notch Interactions Important in Development and Disease?

Abstract

In humans, mutations in the gene for fibrillin‐1 (FBN1) cause both the Marfan syndrome as well as several types of acromelic dysplasias. Musculoskeletal features of the Marfan syndrome (long bone overgrowth and arachnodactyly, joint hypermobility, and a muscle wasting phenotype) are the opposite of those in acromelic dysplasias (short stature and brachydactyly, joint stiffness, and a hypermuscular build). How mutations in the same gene can result in opposite phenotypes is poorly understood. Mutations in FBN2 cause congenital contractural arachnodactyly, which features a mixture of related musculoskeletal features (muscle hypoplasia, contractures of the large and small joints and arachnodactyly).The fibrillins are multifunctional glycoproteins that polymerize into extracellular matrix microfibrils. Although we have associated fibrillin microfibril structure with the opposite musculoskeletal features of Marfan syndrome and acromelic dysplasias, we can only speculate that perturbations in growth factor signaling are involved. To begin to address this gap in our understanding, we hypothesize that direct interactions between fibrillin and cells coordinate growth factor signaling. Therefore, we searched for interactions between fibrillin and cellular receptors.Fibrillins, like Notch receptors and Notch ligands, are composed of multiple tandemly repeated cbEGF‐like domains. Each fibrillin contains 43 cbEGF‐like domains. What if Notch receptors or ligands also bind to fibrillins in the extracellular matrix? Our biochemical data imply that fibrillin interactions with Notch receptors or ligands are just as likely to occur in vivo as interactions between Notch receptors and known Notch transmembrane ligands. Human genetic evidence support significant roles for Notch signaling components in vascular and musculoskeletal diseases, tissues primarily affected in the fibrillinopathies.The current concept of Notch signaling is based strictly on cell‐cell communication. Our investigations have the potential to transform current understanding of context‐dependent Notch signaling by introducing the possibility that Notch signaling components also interact with fibrillin extracellular matrix.Support or Funding Informationgrants from the Shriners Hospitals for Children to Lynn Y. Sakai