Phf 6 disability gene miR - 128 regulates neuronal migration , outgrowth and intrinsic excitability via the intellectual

20 miR-128, a brain-enriched microRNA, has been implicated in the control of 21 neurogenesis and synaptogenesis but its potential roles in intervening processes 22 have not been addressed. We show that post-transcriptional mechanisms restrict 23 miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in 24 adult stem cell niches. Whereas premature miR-128 expression in progenitors for 25 upper layer neurons leads to impaired neuronal migration and inappropriate 26 branching, sponge-mediated inhibition results in overmigration. Within the upper 27 layers, premature miR-128 expression reduces the complexity of dendritic 28 arborization, associated with altered electrophysiological properties. We show that 29 Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann 30 syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression 31 counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and 32 intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a 33 pathway vital for cortical lamination as well as for the development of neuronal 34 morphology and intrinsic excitability. 35