RNA-Binding Protein Hermes/RBPMS Inversely Affects Synapse Density and Axon Arbor Formation in Retinal Ganglion Cells In Vivo

Abstract

The RNA-binding protein Hermes [RNA-binding protein with multiple splicing (RBPMS)] is expressed exclusively in retinal ganglion cells (RGCs) in the CNS, but its function in these cells is not known. Here we show that Hermes protein translocates in granules from RGC bodies down the growing axons. Hermes loss of function in both Xenopus laevis and zebrafish embryos leads to a significant reduction in retinal axon arbor complexity in the optic tectum, and expression of a dominant acting mutant Hermes protein, defective in RNA-granule localization, causes similar defects in arborization. Time-lapse analysis of branch dynamics reveals that the decrease in arbor complexity is caused by a reduction in new branches rather than a decrease in branch stability. Surprisingly, Hermes depletion also leads to enhanced early visual behavior and an increase in the density of presynaptic puncta, suggesting that reduced arborization is accompanied by increased synaptogenesis to maintain synapse number.

hnRNPs Interacting with mRNA Localization Motifs Define AxoNAl RNA Regulons

“…For example, zip-code binding protein 1 (ZBP1, also called IGF-II mRNA binding [IMP1]) protein was shown to bind to a 56 nucleotide (nt) stem-loop structure in the 3' untranslated region (UTR) of β-actin mRNA (Actb), and this binding is necessary for axonal transport of the mRNA (6,7). Other RBPs implicated in axonal mRNA transport include nucleolin (Ncl), HuD (also called ELAVL4), hnRNP Q, hnRNP R, splicing factor proline and glutamine-rich (SFPQ), fragile X mental retardation (FMRP), Hermes, TRF2-S, and TDP-43 proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Despite increased insight into RNA transport and translation, including the identification of literally thousands of axonal mRNAs (18,19), relatively few RBPs have been identified in axons.…”

Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets

“…Dysregulation of RBPMS family proteins has been reported in cancer (Skawran et al 2008;Miller and Stamatoyannopoulos 2010;Drozdov et al 2012;Hapkova et al 2013; http://www.cbioportal.org/public-portal/) and chronic intestinal pseudo-obstruction (Notarnicola et al 2012). Manipulation of RBPMS levels during embryogenesis suggested functions in X. laevis oocyte maturation (Zearfoss et al 2003), heart and kidney development (Gerber et al 2002), and retinal ganglion cell development (Hornberg et al 2013). In X. laevis RBPMS regulated cleavage of vegetal blastomeres in early embryogenesis (Zearfoss et al 2004) and was suggested to control mRNA processing (Gerber et al 2002;Song et al 2007) and transport of mRNAs along the axon to the axon terminal of retinal ganglion cells (Hornberg et al 2013).…”

“…Manipulation of RBPMS levels during embryogenesis suggested functions in X. laevis oocyte maturation (Zearfoss et al 2003), heart and kidney development (Gerber et al 2002), and retinal ganglion cell development (Hornberg et al 2013). In X. laevis RBPMS regulated cleavage of vegetal blastomeres in early embryogenesis (Zearfoss et al 2004) and was suggested to control mRNA processing (Gerber et al 2002;Song et al 2007) and transport of mRNAs along the axon to the axon terminal of retinal ganglion cells (Hornberg et al 2013).…”

RNA-binding protein Rbpms is represented in human retinas by isoforms A and C and its transcriptional regulation involves Sp1-binding site

“…A fascinating, in our opinion, characteristic of the Rbpms expression profile is that although this gene is expressed in various tissues, in the adult CNS, it was restricted to RGCs. In a recent study to investigate the role of Rbpms in the retina, it has been shown that Rbpms loss of function in both Xenopus laevis and zebrafish embryos results in a significant reduction in retinal axon arbor complexity in the optic tectum (Hörnberg et al 2013). At the same time, an increase in the density of presynaptic puncta was observed in these animals, suggesting that reduced arborization is accompanied by increased synaptogenesis to maintain synapse number.…”