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mojdeh abbasi, Vivek Kumar Gupta, Nitin Chitranshi, Stuart L Graham; Mechanistic insights into the PTPN11 actions in the retinal ganglion cells and effects of its loss under glaucoma conditions. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6122. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
SH2 domain-containing tyrosine phosphatase 2 (Shp2; PTPN11) regulates several intracellular pathways downstream of multiple growth factor receptors. Our studies implicate that this phosphatase interacts with Caveolin-1 (Cav-1) protein in the retinal ganglion cells (RGCs) and negatively regulates BDNF/TrkB signaling. This study aimed to examine the in vivo interactions of PTPN11 with Cav-1 specifically in the inner retina by genetically downregulating PTPN11 expression in normal and Cav-1 deficient mice under experimental glaucoma conditions.
PTPN11 was genetically knock downed (KD) in the Cav-1 deficient mice and the age matched wildtype littermates (n=32) using adeno-associated virus (AAV) constructs. AAV expressing PTPN11 shRNA with eGFP under CAG promoter was administered intravitreally while contralateral eyes received AAV-scramble-shRNA as control. Animals were subjected to increased intraocular pressure (IOP) for 2 months through weekly intracameral microbead injections. Changes in inner retinal function were evaluated by measuring positive scotopic threshold response (pSTR) amplitudes. Retinal laminar structural changes were assessed using H&E staining of the retinal sections. All values were compared using Student's t-test for unpaired data. The level of significance was set at P<0.05.
The mice demonstrated increased IOP for 2 months (control, 10.6±0.4; microbead, 25.63±4.7 mmHg). WT mice retinas exposed to high IOP exhibited significantly higher pSTR amplitude when subjected to PTPN11 KD compared to the eyes administered AAV expressing scrambled sequence (n=16, p<0.05). This protection conferred by PTPN11 KD against the inner retinal function deterioration under high IOP was not evident in Cav-1 deficient mice retinas (n=16). Histological assessment revealed that in contrast to the Cav-1 knockout mice where PTPN11 KD in increased IOP exhibited no morphological protection, the ganglion cell layer in the WT mice was significantly protected (n=8, p<0.001).
PTPN11 suppression could impart partial protection to the retina against damage caused by chronic exposure to increased IOP. These results also suggest that protective effects of PTPN11 ablation under experimental glaucoma conditions are dependent on Cav-1, suggesting in vivo interactions between the two proteins.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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