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The Journal of Neuroscience, February 27, 2008, 28(9):2099-2109; doi:10.1523/JNEUROSCI.5092-07.2008

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Development/Plasticity/Repair
Pumilio Binds para mRNA and Requires Nanos and Brat to Regulate Sodium Current in Drosophila Motoneurons

Nara I. Muraro,¹ Andrew J. Weston,² Andre P. Gerber,³ Stefan Luschnig,⁴ Kevin G. Moffat,² and Richard A. Baines¹

¹Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, ²Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom, ³Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule Zurich, CH-8093 Zurich, Switzerland, and ⁴Institute of Zoology, University of Zurich, CH-8057 Zurich, Switzerland

Correspondence should be addressed to either Nara I. Muraro or Richard A. Baines, Faculty of Life Sciences, Stopford 1.124, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Email: nara.muraro{at}manchester.ac.uk or Email: richard.baines{at}manchester.ac.uk

Homeostatic regulation of ionic currents is of paramount importance during periods of synaptic growth or remodeling. Our previous work has identified the translational repressor Pumilio (Pum) as a regulator of sodium current (I_Na) and excitability in Drosophila motoneurons. In this current study, we show that Pum is able to bind directly the mRNA encoding the Drosophila voltage-gated sodium channel paralytic (para). We identify a putative binding site for Pum in the 3' end of the para open reading frame (ORF). Characterization of the mechanism of action of Pum, using whole-cell patch clamp and real-time reverse transcription-PCR, reveals that the full-length protein is required for translational repression of para mRNA. Additionally, the cofactor Nanos is essential for Pum-dependent para repression, whereas the requirement for Brain Tumor (Brat) is cell type specific. Thus, Pum-dependent regulation of I_Na in motoneurons requires both Nanos and Brat, whereas regulation in other neuronal types seemingly requires only Nanos but not Brat. We also show that Pum is able to reduce the level of nanos mRNA and as such identify a potential negative-feedback mechanism to protect neurons from overactivity of Pum. Finally, we show coupling between I_Na (para) and I_K (Shal) such that Pum-mediated change in para results in a compensatory change in Shal. The identification of para as a direct target of Pum represents the first ion channel to be translationally regulated by this repressor and the location of the binding motif is the first example in an ORF rather than in the canonical 3'-untranslated region of target transcripts.

Key words: Pumilio; Nanos; Brat; paralytic; aCC; RP2

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Received Nov. 16, 2007; revised Jan. 10, 2008; accepted Jan. 14, 2008.

Correspondence should be addressed to either Nara I. Muraro or Richard A. Baines, Faculty of Life Sciences, Stopford 1.124, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Email: nara.muraro{at}manchester.ac.uk or Email: richard.baines{at}manchester.ac.uk

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