N onsense-mediated decay (NMD) is a RNA surveillance pathway that degrades subsets of normal and aberrant mRNAs. Mutations that perturb NMD cause neurological disorders in humans, suggesting that NMD has roles in the brain. Recently, it was shown that NMD is repressed during neural development to allow for the stabilization of NMD mRNA targets. The repression of NMD during development is mediated by a neuron-expressed microRNA, miR-128, which participates in a highly conserved regulatory circuit. miR-128 is induced in differentiating neuronal cells and during brain development, leading to repressed NMD and the consequent upregulation of batteries of mRNAs encoding proteins important for neuron differentiation and function. Together with other results, this suggests the existence of a complex network linking the microRNA and NMD pathways that induce cell-specific transcripts. In this point-of-view article, we will discuss the repercussions of this discovery for neuronal development, brain function and disease.Nonsense-mediated mRNA decay (NMD) is a quality control pathway that degrades mutant transcripts with premature termination codons (PTCs).1 More recently, it was discovered that NMD also degrades a subset of transcripts from wild-type genes, leading to the suggestion that NMD is also a post-transcriptional regulatory mechanism.2 Its effects on normal gene expression are extensive, as~3-10% of transcripts are misregulated when NMD is disrupted in a wide range of eukaryotes.3 The normal transcripts targeted by NMD are those that mimic the architecture of aberrant transcripts harboring a PTC. There are many features that can trigger RNA decay by NMD. One of the most common in higher vertebrates is a stop codon followed by an intron. The intron acts as a "second signal" to elicit NMD by virtue of the fact that its removal by RNA splicing recruits a set of proteins collectively called the exon junction complex (EJC) that bind just upstream of the exon-exon junction of the spliced mRNA. When the translating ribosome reaches a stop codon followed by at least one EJC on mature mRNA, this leads to a cascade of events, culminating in the rapid decay of the targeted transcript. Another common NMD-inducing feature present in many normal transcripts is a long 3' UTR. While it is not entirely clear how this feature elicits NMD, recent evidence suggests it increases the probability that a terminating ribosome will interact with NMD factors rather than translation factors to initiate another round of translation. 4,5 In contrast to our increasingly detailed understanding of the underlying mechanism of NMD (reviewed in refs. 1-3), remarkably little is known about its normal roles in organismal physiology and how it is regulated. We recently began to fill this gap by identifying microRNAs (miRNAs) that regulate NMD and promote neuron development.6 miRNAs are endogenous small (~23-nt) RNAs that play important gene-regulatory roles in a variety of eukaryotic organisms by pairing to the mRNAs of protein-coding genes to direct th...