Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt

Genes Dev. 2015 Mar 1;29(5):501-12. doi: 10.1101/gad.258483.115.

Jernej Murn ¹, Kathi Zarnack ², Yawei J Yang ³, Omer Durak ⁴, Elisabeth A Murphy ⁵, Sihem Cheloufi ⁶, Dilenny M Gonzalez ⁵, Marianna Teplova ⁷, Tomaž Curk ⁸, Johannes Zuber ⁹, Dinshaw J Patel ⁷, Jernej Ule ¹⁰, Nicholas M Luscombe ¹¹, Li-Huei Tsai ⁴, Christopher A Walsh ⁵, Yang Shi ¹

Affiliations

1 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA; yang_shi@hms.harvard.edu murn.jernej@gmail.com.
2 European Molecular Biology Laboratory (EMBL) European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany;
3 Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA; Department of Pediatrics, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; yang_shi@hms.harvard.edu murn.jernej@gmail.com.
4 Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
5 Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA; Department of Pediatrics, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;
6 Cancer Center, Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
7 Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
8 Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, Slovenia;
9 The Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria;
10 Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom;
11 European Molecular Biology Laboratory (EMBL) European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom; UCL Genetics Institute, Department of Genetics, Environment, and Evolution, University College London, London WC1E 6BT, United Kingdom; Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom; Okinawa Institute for Science and Technology Graduate University, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan.

PMID: 25737280 DOI: 10.1101/gad.258483.115

Abstract

Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mouse embryos disrupts the shape of migrating neurons, while ectopic expression confers neuronal-like morphology to cells of different nonneuronal lineages. We found that Unkempt is a sequence-specific RNA-binding protein and identified its precise binding sites within coding regions of mRNAs linked to protein metabolism and trafficking. RNA binding is required for Unkempt-induced remodeling of cellular shape and is directly coupled to a reduced production of the encoded proteins. These findings link post-transcriptional regulation of gene expression with cellular shape and have general implications for the development and disease of multicellular organisms.

Keywords

RNA-binding proteins; Unkempt; cell morphology; gene expression program; neurons; translation.

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