Optic neuropathy associated with TGFβ dysregulation in mice with a glaucoma-causative mutation of ADAMTS10

Abstract

Glaucoma is a neurodegenerative disease that causes irreversible blindness due to loss of retinal ganglion cells (RGCs) and their axons. We previously identified a G661R mutation of ADAMTS10 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif 10) as the disease-causing mutation in a beagle model of glaucoma. ADAMTS10 is a secreted matrix metalloproteinase that belongs to the ADAMTS family which is involved in extracellular matrix (ECM) turnover. Previous studies have shown that ADAMTS10 binds fibrillin microfibrils, promotes their formation, and influences their fibrillin isoform composition. Here, we established a mouse model carrying the G661R mutation of ADAMTS10 (ADAMTS10G661R/G661R) to investigate its ocular phenotypes related to glaucoma and to explore possible functions of ADAMTS10. We found that ADAMTS10 was expressed in the inner retina and along RGC axons in the optic nerve. However, ADAMTS10 was not colocalized with fibrillin microfibrils in these tissues, suggesting fibrillin-independent function for ADAMTS10. In electroretinogram experiments, we found that ADAMTS10G661R/G661R mice had reduced amplitude of retinal responses to dim light stimulus, indicating RGC dysfunction. The reduced RGC function coincided with RGC axon structural changes manifested as smaller optic nerves and fewer optic nerve axons, which may contribute to glaucoma. The reduced number of optic nerve axons found for ADAMTS10G661R/G661R mice occurred early, suggesting developmental deficits. Subsequent experiments found increased apoptosis in the retina of ADAMTS10G661R/G661R mice during postnatal development, which could result in fewer RGCs produced, accounting for fewer optic nerve axons in adulthood. Consistent with a protective effect of transforming growth factor β (TGFβ) signaling against apoptosis during retinal development as shown previously by others, we found increased apoptosis accompanied by decreased TGFβ signaling in the developing retina of ADAMTS10G661R/G661R mice, suggesting a novel role for ADAMTS10 in regulating TGFβ signaling which could involve direct interaction between ADAMTS10 and latent TGFβ.