miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6

Abstract

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

Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function

“…Consistent with this prediction, expression of miR-128 by in utero electroporation in the mouse brain arrests the migration of cortical neurons in layers III and IV–VI (Franzoni et al, 2015), which phenocopies the migration defects observed upon PHF6 knockdown (Zhang et al, 2013). Importantly, expression of PHF6 reverses the miR-128-induced migration defects (Franzoni et al, 2015), suggesting that PHF6 operates downstream of miR-128 in the regulation of cortical migration. Whether miR-128 regulation of PHF6 expression influences other aspects of brain development remains to be explored.…”

“…Downregulation of PHF6 expression is correlated with an increase in the expression levels of miR-128, suggesting that miR-128 may regulate PHF6 expression during brain development. Consistent with this interpretation, expression of miR-128 in cortical neurons triggers the downregulation of PHF6, an effect that is mediated by miR-128 binding sites within the 3′UTR of PHF6 mRNA (Franzoni et al, 2015). A prediction of these results is that miR-128 might influence neuronal migration in the cerebral cortex.…”

“…These observations suggest that PHF6 expression is tightly regulated during brain development. Recent studies by Franzoni et al provide insights into the mechanisms underlying the regulation of PHF6 expression (Franzoni et al, 2015). Downregulation of PHF6 expression is correlated with an increase in the expression levels of miR-128, suggesting that miR-128 may regulate PHF6 expression during brain development.…”

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

“…MyoD Prevent difference of postnatal myogenic progenitors [125] miR-128 Phf6, Bmi-1, P70S6K1 Control of neurogenesis and synaptogenesis suppress tumor proliferation and self-renewal [102,126] miR-294…”

“…Moreover, of the last two decades, clinical trials of pharmacological therapeutics either failed to prove efficacy or provided only modest reductions in functional deficits [7][8][9]. Notwithstanding compelling efforts were made to stimulate growth of regenerative axons in experimental SCI models, very limited success had been achieved because of irreversible neuronal loss and glial scar formation [10,11].…”