Developmental abnormalities in the cornea of a mouse model for Marfan syndrome

Eleanor M Feneck,Rodrigo B Souza,Philip N Lewis,Sally Hayes,Lygia V Pereira,Keith M Meek

doi:10.1016/j.exer.2020.108001

Abstract

Elastic fibres provide tissues with elasticity and flexibility. In the healthy human cornea, elastic fibres are limited to the posterior region of the peripheral stroma, but their specific functional role remains elusive.Here, we examine the physical and structural characteristics of the cornea during development in the mgΔloxPneo dominant-negative mouse model for Marfan syndrome, in which the physiological extracellular matrix of its elastic-fibre rich tissues is disrupted by the presence of a dysfunctional fibrillin-1 glycoprotein. Optical coherence tomography demonstrated a reduced corneal thickness in the mutant compared to wild type mice from embryonic day 16.5 until adulthood. X-ray scattering and electron microscopy revealed a disruption to both the elastic fibre and collagen fibril ultrastructure in the knockout mice, as well as abnormally low levels of the proteoglycan decorin. It is suggested that these alterations might be a result of increased transforming growth factor beta signalling. To conclude, this study has demonstrated corneal structure and ultrastructure to be altered when fibrillin-1 is disrupted and has provided insights into the role of fibrillin-1 in developing a functional cornea.

Highlights

Marfan syndrome is an autosomal dominant connective tissue disease caused by mutations in the Fbn-1 gene that encodes the glycoprotein fibrillin-1, the major structural component of microfibrils
At E14.5, measurements of corneal thickness revealed no significant difference between the Fbn1+/− and Wild type (WT) mice
Our previous studies of the adult mgΔloxPneo mouse model, which exhibits some of the phenotypic characteristics associated with Marfan syndrome, identified abnormalities in corneal geometry that were accompanied by irregularities in the organisation of both collagen and elastic fibres within the corneal stroma (White et al, 2017)

Summary

Introduction

Marfan syndrome is an autosomal dominant connective tissue disease caused by mutations in the Fbn-1 gene that encodes the glycoprotein fibrillin-1, the major structural component of microfibrils. These fibres form a scaffold for elastin deposition during the formation of elastic fibres. As has been demonstrated in numerous studies, disruption to the organisation of the collagen and proteoglycans within the extracellular matrix leads to alterations in the strength (Chakravarti et al, 1998), shape (Quantock et al, 2003) and transparency (Quantock et al, 2001) of the tissue. As the truncated fibrillin-1 disrupt microfibril formation and structure, there is a surge in TGF-β signalling

Methods

Results

Conclusion