Optic neuropathy associated with TGFβ dysregulation in mice with a glaucoma-causative mutation of Adamts10

Abstract

Purpose : Beagle dogs homozygous for a G661R mutation in ADAMTS10 develop primary open angle glaucoma. ADAMTS10 is a secreted matrix metalloproteinase that interacts with fibrillin-1 and is thought to promote formation of fibrillin microfibrils in the extracellular matrix. Here, we established a mouse model carrying the G661R mutation of Adamts10 (Adamts10^G661R/G661R) to investigate its ocular phenotypes related to glaucoma and to explore possible functions of ADAMTS10.

Methods : ADAMTS10 and fibrillin-1 expression were examined by immunohistochemistry. Retinal ganglion cell (RGC) function was assessed by positive scotopic threshold response (pSTR) in flash electroretinogram (ERG). Cross-sections of the optic nerves from mice at 3, 6 and 24 months of age were stained with PPD for manual axon quantification using ImageJ. Retinal apoptotic cells at postnatal day 10 were examined by TUNEL assay.

Results : ADAMTS10 immunostaining labeled the retinal nerve fiber layer and RGC axons in the optic nerve where fibrillin-1 was not detected, suggesting fibrillin-independent function for ADAMTS10 in these structures. Adamts10^G661R/G661R mice had reduced pSTR amplitude, indicating RGC dysfunction. The reduced RGC function in Adamts10^G661R/G661R mice 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 for Adamts10^G661R/G661R mice occurred early, suggesting developmental deficits. Subsequent experiments found increased apoptosis in the retina of Adamts10^G661R/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 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 Adamts10^G661R/G661R mice.

Conclusions : The G661R mutation of Adamts10 causes glaucoma-related phenotypes at early age and decreased TGFβ signaling in the developing retina, implying a role of ADAMTS10 in retinal development via regulation of TGFβ signaling.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.