The Neural RNA-Binding Protein Musashi1 Translationally Regulates Mammalian numb Gene Expression by Interacting with Its mRNA

doi:10.1128/MCB.21.12.3888-3900.2001

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Molecular and Cellular Biology, June 2001, p. 3888-3900, Vol. 21, No. 12
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.12.3888-3900.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Neural RNA-Binding Protein Musashi1 Translationally Regulates Mammalian numb Gene Expression by Interacting with Its mRNA

Takao Imai,¹^,²^,³ Akinori Tokunaga,¹^,² Tetsu Yoshida,¹^,² Mitsuhiro Hashimoto,⁴ Katsuhiko Mikoshiba,⁴^,⁵ Gerry Weinmaster,⁶^,⁷ Masato Nakafuku,⁸^,⁹ and Hideyuki Okano¹^,²^,⁹^,^*

Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582,¹ Division of Neuroanatomy (D12), Department of Neuroscience, Osaka University Graduate School of Medicine,² and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Suita 565-0871, Osaka,⁹ Laboratory of Neuroscience, Division of Biophysical Engineering, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531,³ Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute (BSI), Wako, Saitama 351-0198,⁴ Department of Molecular Neurobiology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639,⁵ Department of Neurobiology, The University of Tokyo, Graduate School of Medicine, Tokyo 113-0033,⁸ Japan, and Department of Biological Chemistry, UCLA School of Medicine,⁶ and Molecular Biology Institute, University of California,⁷ Los Angeles, California 90095

Received 8 December 2000/Returned for modification 17 January 2001/Accepted 20 March 2001

Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural progenitor cells, including neural stem cells.In this study, the RNA-binding sequences for Msi1 were determinedby in vitro selection using a pool of degenerate 50-mer sequences.All of the selected RNA species contained repeats of (G/A)U_nAGU(n = 1 to 3) sequences which were essential for Msi1 binding.These consensus elements were identified in some neural mRNAs.One of these, mammalian numb (m-numb), which encodes a membrane-associatedantagonist of Notch signaling, is a likely target of Msi1. Msi1protein binds in vitro-transcribed m-numb RNA in its 3'-untranslatedregion (UTR) and binds endogenous m-numb mRNA in vivo, as shownby affinity precipitation followed by reverse transcription-PCR.Furthermore, adenovirus-induced Msi1 expression resulted in thedown-regulation of endogenous m-Numb protein expression. Reporterassays using a chimeric mRNA that combined luciferase and the3'-UTR of m-numb demonstrated that Msi1 decreased the reporteractivity without altering the reporter mRNA level. Thus, our resultssuggested that Msi1 could regulate the expression of its targetgene at the translational level. Furthermore, we found that Notchsignaling activity was increased by Msi1 expression in connectionwith the posttranscriptional down-regulation of the m-numbgene.

^* Corresponding author. Mailing address: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku,Tokyo 160-8582, Japan. Phone: 81-3-5363-3746. Fax: 81-3-3357-5445.E-mail: hidokano{at}med.keio.ac.jp.

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