FOXP2-Dependent Vulnerability of RGCs Under Acute Ocular Hypertension.

Acute angle-closure glaucoma leads to a rapid rise in intraocular pressure. Ocular hypertension (OHT) compresses the optic nerve head and causes degeneration of retinal ganglion cells (RGCs). RGC subtypes exhibit different susceptibility to OHT. This study aimed to determine whether the selective vulnerability of RGCs is related to Foxp2, a critical gene in neurodevelopmental disorders and neurodegeneration. Acute OHT increased apoptotic cell death of RGCs and reduced the ratio of FOXP2-positive RGCs (F-RGCs) to the total RGCs, suggesting a higher proportional loss of F-RGCs compared to average non-F-RGCs. Retina-specific knockout (KO) of Foxp2 in mice mitigated the excessive reduction of F-RGCs and degeneration of RGC axons (blebbing) caused by acute OHT. Furthermore, F-RGCs had an increased expression of dynactin-1, and their soma received retrograde labeling from the superior colliculus at a slower rate than the non-F-RGCs, suggesting that FOXP2 may impair the dynactin/dynein-mediated axoplasmic transport in RGCs. The data support that Foxp2 contributes to increased vulnerability of RGCs to OHT-induced damage, at least in part by slowing axonal transport. This study sheds light on the molecular mechanisms governing RGCs' selective vulnerability and provides insights into potential strategies to protect these cells from OHT in glaucoma.