Regulation of microRNA function in rodent hippocampal neurons by an alternative Ube3a transcript
The activity-dependent regulation of neuronal maturation is important for the development of neural circuits and cognition. Defects in this process lead to severe neurodevelopmental disorders associated with intellectual disability and autism (Kuczewski et al., 2010). UBE3A has been previously demo...
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|The activity-dependent regulation of neuronal maturation is important for the development of neural circuits and cognition. Defects in this process lead to severe neurodevelopmental disorders associated with intellectual disability and autism (Kuczewski et al., 2010).
UBE3A has been previously demonstrated to control important aspects of neuronal maturation. UBE3A loss-of-function mutations cause Angelman syndrome (AS) (Kishino et al., 1997), whereas increased UBE3A gene dosage has been associated with autism-spectrum disorders (ASD) (Glessner et al., 2009).
The UBE3A gene encodes an enzyme with ubiquitin ligase activity which is important for the degradation of neuronal proteins by the ubiquitin proteasome system. However, defects in UBE3A enzymatic activity unlikely account for the full spectrum of AS and ASD cases, since rare mutations outside the coding region have been identified (Bird, 2014).
Recently, several alternative Ube3a transcripts have been described that include variable 5' and 3' ends, suggesting complex post-transcriptional regulation of Ube3a expression. In particular, the different 3’UTRs present in Ube3a 3' variants could be used for differential regulation of mRNA localization and translation. However, little was known concerning expression, localization and regulatory functions of the alternative Ube3a transcripts.
In this work, I discovered that the rodent Ube3a1-RNA, which contains a truncated coding sequence and an alternative 3'UTR, has unique functions in neuronal maturation and a gene regulatory function that strongly differ from functions of the transcripts that code for the active Ube3a enzyme.
Ube3a1-RNA is specifically increased by elevated neuronal activity and preferentially localizes to neuronal dendrites. Opposite to Ube3a enzyme-coding transcripts, Ubea1 is a negative regulator of dendrite outgrowth in rodent hippocampal neurons both in dissociated neuronal cultures and in vivo. In addition, Ube3a1 is necessary for dendritic spine maturation in cultured hippocampal neurons. Surprisingly, I found that the function of Ube3a1-RNA in the context of dendrite outgrowth was coding-independent and could be attributed to the presence of the alternative 3'UTR.
Considering the molecular mechanisms underlying Ube3a1-RNA function, I found that the Ube3a1-RNA 3’UTR is a target of several microRNAs encoded by the miR-379/410 cluster, including miR-134 that was previously implicated in dendritogenesis and spine maturation. However, Ube3a1-RNA is not regulated by miRNAs in a canonical manner, but rather competes with other miR-379/410 target mRNAs for binding to common miRNAs. Therefore, Ube3a1-RNA can be considered as a competing endogenous RNA (ceRNA) following a hypothesis that was previously put forward in cancer cell lines. (Salmena et al., 2011)
In conclusion, the results from my thesis describe a new gene regulatory mechanism operating in neuronal dendrites with important implications for neuronal maturation, circuit development and neurodevelopmental disorders.