title: Retinoid receptors trigger neuritogenesis in retinal degenerations.
abstract: 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 β Ca(2+)/calmodulin-dependent protein kinase II (βCaMKII). Pulldown assays demonstrated interaction between βCaMKII 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.
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Lin
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Jones
authors.forename: Aihua
authors.initials: A
authors.lastname: Liu
authors.forename: James F
authors.initials: JF
authors.lastname: Tucker
authors.forename: Kevin
authors.initials: K
authors.lastname: Rapp
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Carl B
authors.initials: CB
authors.lastname: Watt
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Yang
authors.forename: Marguerite V
authors.initials: MV
authors.lastname: Shaw
authors.forename: Robert E
authors.initials: RE
authors.lastname: Marc
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics; D000077556:Alitretinoin; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D018091:Receptors, AMPA / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism; D014785:Vision, Ocular / Q000502:physiology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000429:Alcohol Oxidoreductases; D000077556:Alitretinoin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018091:Receptors, AMPA; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta; C022520:retinol dehydrogenase; C104722:glutamate receptor ionotropic, AMPA 2