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Carolina Pinzon-Guzman, Samuel S. Zhang, Colin J. Barnstable; IGF1 Promotes Rod Photoreceptor Development By Activating Protein Kinase C (pkc) Beta 1 And Gamma Isoforms. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5419.
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Both intrinsic and extrinsic signals regulate rod photoreceptor development. We have previously shown that PKC activation promotes rod differentiation through inhibition of STAT3 function. In some areas of the CNS IGF1 has been shown to be essential for correct development (Accili et al 1996) (Lieu et al 1993). Here we test the hypothesis that IGF1 promotes rod differentiation by activating PKC. In addition we investigate the signal cascade involved in IGF1 promotion of rods.
Animal use was in accordance with ARVO/IACUC guidelines. Retinal explant cultures were established from P1 wild type and PKC Gamma knockout mice (Jackson laboratories) in serum free medium (Ultraculture, Lonza) with L-glutamine and antibiotics and kept for 1 to 8 days. PMA (100nM), LIF (20ng/mL), specific PKC Beta 1 inhibitor LY 333531 (30nM), and a specific inhibitor of PI3Kinase Ly294002 (50µM) were added to the culture medium 2 hours after explant isolation. Treated and control retina samples were collected for immunohistochemistry and western blots.
IGF1 treatment increased the number of opsin positive cells in explants by an average of four fold. This effect was partially reduced when either PKC Beta 1 or PKC Gamma was inhibited, but was completely abolished when both PKC B1 and PKC Gamma activities were inhibited. IGF1 signaling generally involves activation of PI3Kinase (PI3K) and AKT. Inhibition of AKT function did not alter the effect of IGF1 on rod development. However, inhibition of PI3K activity stimulated differentiation of rods to a greater extent than IGF1 treatment. This increase in rods following inhibition of PI3K activity was also PKC dependent. As expected IGF1 treatment of adult retinas led to increased phosphorylation of AKT. However, IGF1 treatment of P1 retinas led to a decrease in phosphorylation of AKT.
IGF-1 increases rod formation in neonatal mouse retinas in a PKC dependent pathway. Our pharmacological results suggest that IGF1 initiates this effect through inhibition of the PI3K transduction pathway.
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