Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt.
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.
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.
Jernej
J
Murn
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;
Kathi
K
Zarnack
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.
Yawei J
YJ
Yang
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Omer
O
Durak
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;
Elisabeth A
EA
Murphy
Cancer Center, Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
Sihem
S
Cheloufi
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;
Dilenny M
DM
Gonzalez
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
Marianna
M
Teplova
Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, Slovenia;
Tomaž
T
Curk
The Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria;
Johannes
J
Zuber
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
Dinshaw J
DJ
Patel
Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom;
Jernej
J
Ule
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.
Nicholas M
NM
Luscombe
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Li-Huei
LH
Tsai
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;
Christopher A
CA
Walsh
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.
Yang
Y
Shi
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D048430:Cell Shape / Q000235:genetics*; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology*; D011485:Protein Binding; D012333:RNA, Messenger
D012333:RNA, Messenger
RNA-binding proteins; Unkempt; cell morphology; gene expression program; neurons; translation