Retinoid Receptors Trigger Neuritogenesis in Retinal Degenerations

This paper by Y Lin, BW Jones, A Liu, JF Tucker, K Rapp, L Luo, W Baehr, PS Bernstein, CB Watt, JH Yang, MV Shaw and RE Marc examines the neuronal sprouting or neuritogenesis components of retinal remodeling found in retinal degenerative disease and describes a control process for retinoid X receptors (RXRs) in neuritogenesis. 

Neuritogenesis or outgrowth of dendrites and axons is an important part of neuronal maturation during the development of central nervous system (CNS), including retina.  The precise lamination and patterning of retina is established early on in development and is thought to form relatively static connections that define normal retinal circuitry.  However, in retinal degenerative (RD) disease, adult-onset neurite outgrowth is activated in RD diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP).  Retinal degeneration induced neurite outgrowth is considered negative plasticity and represents a barrier to vision rescue strategies, as the new neuritic outgrowths are synaptically active and corruptive of normal retinal processing.  Therefore, uncovering the molecular mechanisms underlying RD induced neurite outgrowth has the potential to attenuate neurite outgrowth and stabilize the retina for future vision rescue strategies.

This paper describes RXR mechanisms in retinal degeneration induced neurite outgrowth using a light-induced retinal degeneration (LIRD) model, which found that LIRD rapidly triggered retinal neuron neurite outgrowth and up-regulated the protein levels of several key elements of retinoic acid (RA) signaling (retinoic acid → cellular retinoic acid binding protein II → retinoic acid receptors/retinoid X receptors).  Exogenous RA initiates neurite outgrowth in normal adult retinas and primary retinal cultures and exacerbates neuritic outgrowth in LIRD retinas.  Consistently, LIRD-induced neurite outgrowth was attenuated in retinol dehydrogenase knockout (Rdh12(-/-)) mice, which have lower levels of retinoic acid, demonstrating that retinoic acid signaling is involved in RD-induced neurite outgrowth.  The paper further describes citral (an inhibitor of in vivo retinoic acid synthesis) does not completely inhibit RD-induced neurite outgrowth, suggesting that other pathways besides retinoic acid signaling are involved in RD-induced neurite outgrowth.  The paper then describes protein interactions between Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and retinoid X receptors, suggesting that CaMKII pathway regulates the activities of retinoid X receptors.  It turns out that retinoid X receptor agonists were more effective than retinoic acid in inducing neurite outgrowth, while retinoid X receptors antagonists completely prevented RD-induced neurite outgrowth.  Thus, retinoid X receptors are in the final common path and may be therapeutic targets to attenuate RD-induced neurite outgrowth and facilitate intervention methods in blinding diseases.