miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability.DOI: http://dx.doi.org/10.7554/eLife.04263.001

About half of mammalian miRNA genes lie within introns of protein-coding genes, yet little is known about functional interactions between miRNAs and their host genes. The intronic miRNA miR-128 regulates neuronal excitability and dendritic morphology of principal neurons during mouse cerebral cortex development. Its conserved host genes, R3hdm1 and Arpp21, are predicted RNA-binding proteins. Here we use iCLIP to characterize ARPP21 recognition of uridine-rich sequences with high specificity for 3′UTRs. ARPP21 antagonizes miR-128 activity by co-regulating a subset of miR-128 target mRNAs enriched for neurodevelopmental functions. Protein–protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F. This molecular antagonism is reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. Thus, we describe a unique example of convergent function by two products of a single gene.

The purpose of this experiment was the demonstration of conditioned stress-induced analgesia in humans. Following a baseline day (day 1), two groups of 10 subjects were each exposed to green light as the conditioned stimulus (CS) and mental arithmetic plus noise as the unconditioned stimulus (US) for 5 days (days 2-6), a third group of 10 subjects was only exposed to the US. On the test day (day 7), pain threshold and pain tolerance were tested, while groups 1 and 3 received the green light CS and group 2 received no CS. Group 1 showed a significantly higher pain threshold and higher pain tolerance on the test day, whereas the two control groups did not have altered pain perception. Heart rate data confirmed successful stress induction. Heart rate and blood pressure were unaltered on the test day, thus making cardiovascular mediation of the conditioning effect unlikely. Conditioned stress analgesia might be useful in the understanding of chronic pain-syndromes. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.