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

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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.

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Eleonora Franzoni

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Sam A Booker

Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Srinivas Parthasarathy

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Frederick Rehfeld

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Sabine Grosser

Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Swathi Srivatsa

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Heiko R Fuchs

Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, Düsseldorf, Germany

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The authors declare that no competing interests exist.
Victor Tarabykin

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Imre Vida

Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
F Gregory Wulczyn

Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

For correspondence
gregory.wulczyn@charite.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were conducted according to the European and German laws, in conformance with the Animal Welfare Act and the European legislative Directives 86/609/EEC 2010/63/EU from 2010 on as updated in 2013. The animal welfare committee of the Charité, Berlin, approved and supervised the experiments performed under the experimental license number T01012/11. All surgery was performed using Isofluran as anesthetic and Temgesic® for analgesia as required to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.