title: Characterization of neurite outgrowth and ectopic synaptogenesis in response to photoreceptor dysfunction.
abstract: In the mammalian retina, light signals generated in photoreceptors are passed to bipolar and horizontal cells via synaptic contacts. In various pathological conditions, these second-order neurons extend neurites into the outer nuclear layer (ONL). However, the molecular events associated with this neurite outgrowth are not known. Here, we characterized the morphological synaptic changes in the CNGA3/CNGB1 double-knockout (A3B1) mouse, a model of retinitis pigmentosa. In these mice, horizontal cells looked normal until postnatal day (p) 11, but started growing neurites into the ONL 1 day later. At p28, the number of sprouting processes decreased, but the remaining sprouts developed synapse-like contacts at rod cell bodies, with an ultrastructural appearance reminiscent of ribbon synapses. Hence, neurite outgrowth and ectopic synaptogenesis in the A3B1 retina were precisely timed events starting at p12 and p28, respectively. We therefore performed microarray analysis of retinal gene expression in A3B1 and wild-type mice at those ages to evaluate the genomic response underlying these two events. This analysis identified 163 differentially regulated genes in the A3B1 retina related to neurite outgrowth or plasticity of synapses. The global changes in gene expression in the A3B1 retina were consistent with activation of signaling pathways related to Tp53, Smad, and Stat3. Moreover, key molecules of these signaling pathways could be localized at or in close proximity to outgrowing neurites. We therefore propose that Tp53, Smad, and Stat3 signaling pathways contribute to the synaptic plasticity in the A3B1 retina.
authors.affiliation: Center for Integrated Protein Science Munich CiPSM and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr 7, 81377, Munich, Germany. michalakis@lmu.de
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Karin
authors.initials: K
authors.lastname: Schäferhoff
authors.forename: Isabella
authors.initials: I
authors.lastname: Spiwoks-Becker
authors.forename: Nawal
authors.initials: N
authors.lastname: Zabouri
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.forename: Fred
authors.initials: F
authors.lastname: Koch
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Silke
authors.initials: S
authors.lastname: Haverkamp
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D009473:Neuronal Plasticity; D012160:Retina / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000378:metabolism* / Q000473:pathology; D051248:Retinal Horizontal Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C518237:Cnga3 protein, mouse; C529481:Cngb1 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; D016159:Tumor Suppressor Protein p53