Retinoid receptors trigger neuritogenesis in retinal degenerations

Anomalous neuritogenesis is a hallmark of neurodegenerative disorders, including retinal degenerations, epilepsy, and Alzheimer's disease. The neuritogenesis processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented retina and brain regions. Using the light-induced retinal degeneration (LIRD) mouse model, which provides a unique platform for exploring the mechanisms underlying neuritogenesis, we found that retinoid X receptors (RXRs) control neuritogenesis. LIRD rapidly triggered retinal neuron neuritogenesis and up-regulated several key elements of retinoic acid (RA) signaling, including retinoid X receptors (RXRs). Exogenous RA initiated neuritogenesis in normal adult retinas and primary retinal cultures and exacerbated it in LIRD retinas. However, LIRD-induced neuritogenesis was partly attenuated in retinol dehydrogenase knockout (Rdh12(-/-)) mice and by aldehyde dehydrogenase inhibitors. We further found that LIRD rapidly increased the expression of glutamate receptor 2 and beta Ca2+/calmodulin-dependent protein kinase II (beta CaMKII). Pull-down assays demonstrated interaction between beta CaMKII and RXRs, suggesting that CaMKII pathway regulates the activities of RXRs. RXR antagonists completely prevented and RXR agonists were more effective than RA in inducing neuritogenesis. Thus, RXRs are in the final common path and may be therapeutic targets to attenuate retinal remodeling and facilitate global intervention methods in blinding diseases and other neurodegenerative disorders.-Lin, Y., Jones, B. W., Liu, A., Tucker, J. F., Rapp, K., Luo, L., Baehr, W., Bernstein, P. S., Watt, C. B., Yang, J.-H., Shaw, M. V., Marc, R. E. Retinoid receptors trigger neuritogenesis in retinal degenerations. FASEB J. 26, 81-92 (2012). www.fasebj.org