Convergence of the MicroRNA and NMD Pathways in Neurons

Abstract

Nonsense‐mediated RNA decay (NMD) was originally identified to degrade “nonsense” mRNAs, but since then it has become clear that it also regulates ~10% of wild‐type transcripts. This regulatory role suggests that NMD itself is subject to regulation. Indeed, we recently identified a conserved regulatory circuit in mature neurons that regulates NMD through the ability of the microRNA miR‐128 to repress the NMD factors UPF1 and MLN51. Here, we report the identification of another microRNA miR‐9, which is expressed during neurogenesis, that regulates NMD by targeting UPF3B. Loss of UPF3B was recently shown to cause intellectual disability (ID) in humans. First, using reporter constructs, we obtained both gain‐and loss‐of‐function evidence that the UPF3B 3′UTR is regulated by miR‐9. Second, we found that endogenous UPF3B transcripts in cell lines are regulated by miR‐9. This miR‐9‐UPF3B circuit is likely to be physiologically relevant, as we observed that miR‐9 and UPF3B are colocalized in neurons in many regions of the mouse brain. We propose that the regulation of UPF3B by miR‐9 is important in neurogenesis. This may be disrupted in several human diseases, as mutations in human UPF3B are found not only in ID patients, but those with psychological disorders, including autism and schizophrenia.Research Supported by NIH