A coding-independent function of an alternative Ube3a transcript during neuronal development

Abstract

The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.

MicroRNAs in neural development: from master regulators to fine-tuners

“…Different RNA classes can function as miRNA sponges, e.g. the 3′ UTR of mRNAs such as Ube3a-1 (Valluy et al, 2015), long non-coding RNAs (lncRNAs) such as LncND (lncRNA termed neurodevelopment) (Rani et al, 2016) or circular RNAs (circRNAs) such as ciRS-7 (also known as CDR1as), which is highly and selectively expressed in hippocampal and neocortical neurons and contains >70 binding sites for the neuronal miR-7 and one perfectly complementary site for miR-671 (Hansen et al, 2013;Memczak et al, 2013). (5) Regulation of the composition and activity of the neuronal miRISC.…”

CncRNAs: RNAs with both coding and non-coding roles in development

“…Alternative splicing can also generate different RNA isoforms, some of which may retain the coding activity whereas others might function as non-coding RNAs. This has been observed for SRA RNA and UBE3 RNA, whereby alternative splicing leads to retention of an intron and disruption of the ORF, generating the noncoding version of these transcripts (Lanz et al, 1999;Hube et al, 2011;Valluy et al, 2015). Thus, in addition to increasing the protein-coding capacity of genomes by generating peptide isoforms, alternative splicing can also generate a variety of non-coding RNA isoforms.…”

“…Finally, a recent study reports that transcripts encoding the E3 ubiquitin ligase UBE3A have a non-coding role in dendrite growth and spine maturation in hippocampal neurons; by contrast, UBE3A protein plays crucial roles in activity-dependent synapse development, plasticity, learning and memory (Sun et al, 2015;Valluy et al, 2015). This role was discovered using antisense short hairpin RNAs (shRNAs) that target Ube3a 3′UTR variants in rat hippocampal neurons: the neurons showed significantly increased dendrite growth and complexity upon knockdown of the non-translated and intron-retaining Ube3a1 RNA, whereas shRNAs targeting the spliced coding Ube3a2/3 isoforms reduced dendrite complexity (Valluy et al, 2015).…”

“…This role was discovered using antisense short hairpin RNAs (shRNAs) that target Ube3a 3′UTR variants in rat hippocampal neurons: the neurons showed significantly increased dendrite growth and complexity upon knockdown of the non-translated and intron-retaining Ube3a1 RNA, whereas shRNAs targeting the spliced coding Ube3a2/3 isoforms reduced dendrite complexity (Valluy et al, 2015). Antisense oligonucleotides can have off-target effects or, alternatively, they can uncover novel mechanisms not identified by protein-disrupting mutants.…”

“…1). For example, non-coding Ube3a1 RNA retains an intron and is thought to act as a decoy or molecular sponge for miRNA-134 (MIR134) that would otherwise target the spliced Ube3a2/3 transcripts and downregulate UBE3A ubiquitin ligase protein expression in dendrites (Valluy et al, 2015).…”