Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (35): 12449-12454

Copyright © 2005 by the National Academy of Sciences.

From the Cover


MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision

Robert J. Johnston, Jr., Sarah Chang, John F. Etchberger, Christopher O. Ortiz, and Oliver Hobert *

Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Howard Hughes Medical Institute, Columbia University Medical Center, 701 West 168th Street, New York, NY 10032

Communicated by Thomas M. Jessell, Columbia University College of Physicians and Surgeons, New York, NY, July 12, 2005

Received for publication April 27, 2005.

Abstract: The elucidation of the architecture of gene regulatory networks that control cell-type specific gene expression programs represents a major challenge in developmental biology. We describe here a cell fate decision between two alternative neuronal fates and the architecture of a gene regulatory network that controls this cell fate decision. The two Caenorhabditis elegans taste receptor neurons "ASE left" (ASEL) and "ASE right" (ASER) share many bilaterally symmetric features, but each cell expresses a distinct set of chemoreceptors that endow the gustatory system with the capacity to sense and discriminate specific environmental inputs. We show that these left/right asymmetric fates develop from a precursor state in which both ASE neurons express equivalent features. This hybrid precursor state is unstable and transitions into the stable ASEL or ASER terminal end state. Although this transition is spatially stereotyped in wild-type animals, mutant analysis reveals that each cell has the potential to transition into either the ASEL or ASER stable end state. The stability and irreversibility of the terminal differentiated state is ensured by the interactions of two microRNAs (miRNAs) and their transcription factor targets in a double-negative feedback loop. Simple feedback loops are found as common motifs in many gene regulatory networks, but the loop described here is unusually complex and involves miRNAs. The interaction of miRNAs in double-negative feedback loops may not only be a means for miRNAs to regulate their own expression but may also represent a general paradigm for how terminal cell fates are selected and stabilized.

Key Words: left/right asymmetry • bistable • network motif • regulatory RNA • cellular diversification

Author contributions: R.J.J., S.C., J.F.E., and C.O.O. performed research; R.J.J., S.C., J.F.E., C.O.O., and O.H. analyzed data; O.H. designed research; and O.H. wrote the paper.

Abbreviations: ASEL, ASE left; ASER, ASE right; miRNA, microRNA.

* To whom correspondence should be addressed. E-mail: or38{at}

© 2005 by The National Academy of Sciences of the USA

Pre-dispositions and epigenetic inheritance in the Escherichia coli lactose operon bistable switch.
L. Robert, G. Paul, Y. Chen, F. Taddei, D. Baigl, and A. B. Lindner (2014)
Mol Syst Biol 6, 357
   Abstract »    Full Text »    PDF »
Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1.
L. Cochella, B. Tursun, Y.-W. Hsieh, S. Galindo, R. J. Johnston, C.-F. Chuang, and O. Hobert (2014)
Genes & Dev. 28, 34-43
   Abstract »    Full Text »    PDF »
Transcription factor and microRNA co-regulatory loops: important regulatory motifs in biological processes and diseases.
H.-M. Zhang, S. Kuang, X. Xiong, T. Gao, C. Liu, and A.-Y. Guo (2013)
Brief Bioinform
   Abstract »    Full Text »    PDF »
A Feedback Loop Consisting of MicroRNA 23a/27a and the {beta}-Like Globin Suppressors KLF3 and SP1 Regulates Globin Gene Expression.
Y. Ma, B. Wang, F. Jiang, D. Wang, H. Liu, Y. Yan, H. Dong, F. Wang, B. Gong, Y. Zhu, et al. (2013)
Mol. Cell. Biol. 33, 3994-4007
   Abstract »    Full Text »    PDF »
Functional characterization of bacterial sRNAs using a network biology approach.
S. R. Modi, D. M. Camacho, M. A. Kohanski, G. C. Walker, and J. J. Collins (2011)
PNAS 108, 15522-15527
   Abstract »    Full Text »    PDF »
A Left/Right Asymmetric Neuronal Differentiation Program Is Controlled by the Caenorhabditis elegans LSY-27 Zinc-Finger Transcription Factor.
F. Zhang, M. M. O'Meara, and O. Hobert (2011)
Genetics 188, 753-759
   Abstract »    Full Text »    PDF »
Otx-dependent expression of proneural bHLH genes establishes a neuronal bilateral asymmetry in C. elegans.
S. Nakano, R. E. Ellis, and H. R. Horvitz (2010)
Development 137, 4017-4027
   Abstract »    Full Text »    PDF »
Maintenance of Neuronal Laterality in Caenorhabditis elegans Through MYST Histone Acetyltransferase Complex Components LSY-12, LSY-13 and LIN-49.
M. M. O'Meara, F. Zhang, and O. Hobert (2010)
Genetics 186, 1497-1502
   Abstract »    Full Text »    PDF »
MicroRNA-221 Regulates Chondrogenic Differentiation through Promoting Proteosomal Degradation of Slug by Targeting Mdm2.
D. Kim, J. Song, and E.-J. Jin (2010)
J. Biol. Chem. 285, 26900-26907
   Abstract »    Full Text »    PDF »
The homeodomain protein hmbx-1 maintains asymmetric gene expression in adult C. elegans olfactory neurons.
B. J. Lesch and C. I. Bargmann (2010)
Genes & Dev. 24, 1802-1815
   Abstract »    Full Text »    PDF »
The Groucho ortholog UNC-37 interacts with the short Groucho-like protein LSY-22 to control developmental decisions in C. elegans.
E. B. Flowers, R. J. Poole, B. Tursun, E. Bashllari, I. Pe'er, and O. Hobert (2010)
Development 137, 1799-1805
   Abstract »    Full Text »    PDF »
Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping.
M. L. Bell, M. Buvoli, and L. A. Leinwand (2010)
Mol. Cell. Biol. 30, 1937-1945
   Abstract »    Full Text »    PDF »
Dicer Is Required for the Transition from Early to Late Progenitor State in the Developing Mouse Retina.
S. A. Georgi and T. A. Reh (2010)
J. Neurosci. 30, 4048-4061
   Abstract »    Full Text »    PDF »
Making a difference together: reciprocal interactions in C. elegans and zebrafish asymmetric neural development.
R. W. Taylor, Y.-W. Hsieh, J. T. Gamse, and C.-F. Chuang (2010)
Development 137, 681-691
   Abstract »    Full Text »    PDF »
Neuron-type specific regulation of a 3'UTR through redundant and combinatorially acting cis-regulatory elements.
D. Didiano, L. Cochella, B. Tursun, and O. Hobert (2010)
RNA 16, 349-363
   Abstract »    Full Text »    PDF »
Single-cell transcriptional analysis of taste sensory neuron pair in Caenorhabditis elegans.
J. Takayama, S. Faumont, H. Kunitomo, S. R. Lockery, and Y. Iino (2010)
Nucleic Acids Res. 38, 131-142
   Abstract »    Full Text »    PDF »
Cis-regulatory Mutations in the Caenorhabditis elegans Homeobox Gene Locus cog-1 Affect Neuronal Development.
M. M. O'Meara, H. Bigelow, S. Flibotte, J. F. Etchberger, D. G. Moerman, and O. Hobert (2009)
Genetics 181, 1679-1686
   Abstract »    Full Text »    PDF »
Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C. elegans.
J. F. Etchberger, E. B. Flowers, R. J. Poole, E. Bashllari, and O. Hobert (2009)
Development 136, 147-160
   Abstract »    Full Text »    PDF »
The Caenorhabditis elegans vulva: A post-embryonic gene regulatory network controlling organogenesis.
T. O. Ririe, J. S. Fernandes, and P. W. Sternberg (2008)
PNAS 105, 20095-20099
   Abstract »    Full Text »    PDF »
MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F, and Myc.
B. D. Aguda, Y. Kim, M. G. Piper-Hunter, A. Friedman, and C. B. Marsh (2008)
PNAS 105, 19678-19683
   Abstract »    Full Text »    PDF »
Genome-scale spatiotemporal analysis of Caenorhabditis elegans microRNA promoter activity.
N. J. Martinez, M. C. Ow, J. S. Reece-Hoyes, M. I. Barrasa, V. R. Ambros, and A. J.M. Walhout (2008)
Genome Res. 18, 2005-2015
   Abstract »    Full Text »    PDF »
Analysis of regulatory network topology reveals functionally distinct classes of microRNAs.
X. Yu, J. Lin, D. J. Zack, J. T. Mendell, and J. Qian (2008)
Nucleic Acids Res. 36, 6494-6503
   Abstract »    Full Text »    PDF »
A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity.
N. J. Martinez, M. C. Ow, M. I. Barrasa, M. Hammell, R. Sequerra, L. Doucette-Stamm, F. P. Roth, V. R. Ambros, and A. J.M. Walhout (2008)
Genes & Dev. 22, 2535-2549
   Abstract »    Full Text »    PDF »
Stochasticity and Cell Fate.
R. Losick and C. Desplan (2008)
Science 320, 65-68
   Abstract »    Full Text »    PDF »
Gene Regulation by Transcription Factors and MicroRNAs.
O. Hobert (2008)
Science 319, 1785-1786
   Abstract »    Full Text »    PDF »
Identification of phylogenetically conserved microRNA cis-regulatory elements across 12 Drosophila species.
X. Wang, J. Gu, M. Q. Zhang, and Y. Li (2008)
Bioinformatics 24, 165-171
   Abstract »    Full Text »    PDF »
MicroRNA Let-7a Down-regulates MYC and Reverts MYC-Induced Growth in Burkitt Lymphoma Cells.
V. B. Sampson, N. H. Rong, J. Han, Q. Yang, V. Aris, P. Soteropoulos, N. J. Petrelli, S. P. Dunn, and L. J. Krueger (2007)
Cancer Res. 67, 9762-9770
   Abstract »    Full Text »    PDF »
A simple array platform for microRNA analysis and its application in mouse tissues.
X. Tang, J. Gal, X. Zhuang, W. Wang, H. Zhu, and G. Tang (2007)
RNA 13, 1803-1822
   Abstract »    Full Text »    PDF »
Genetic Screens for Caenorhabditis elegans Mutants Defective in Left/Right Asymmetric Neuronal Fate Specification.
S. Sarin, M. M. O'Meara, E. B. Flowers, C. Antonio, R. J. Poole, D. Didiano, R. J. Johnston Jr., S. Chang, S. Narula, and O. Hobert (2007)
Genetics 176, 2109-2130
   Abstract »    Full Text »    PDF »
PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation.
G. C. Coutinho-Mansfield, Y. Xue, Y. Zhang, and X.-D. Fu (2007)
Genes & Dev. 21, 1573-1577
   Full Text »    PDF »
A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.
P. L. Boutz, P. Stoilov, Q. Li, C.-H. Lin, G. Chawla, K. Ostrow, L. Shiue, M. Ares Jr., and D. L. Black (2007)
Genes & Dev. 21, 1636-1652
   Abstract »    Full Text »    PDF »
The molecular signature and cis-regulatory architecture of a C. elegans gustatory neuron.
J. F. Etchberger, A. Lorch, M. C. Sleumer, R. Zapf, S. J. Jones, M. A. Marra, R. A. Holt, D. G. Moerman, and O. Hobert (2007)
Genes & Dev. 21, 1653-1674
   Abstract »    Full Text »    PDF »
The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells.
P. Laneve, L. Di Marcotullio, U. Gioia, M. E. Fiori, E. Ferretti, A. Gulino, I. Bozzoni, and E. Caffarelli (2007)
PNAS 104, 7957-7962
   Abstract »    Full Text »    PDF »
MicroRNAs in biological processes and carcinogenesis.
H. Osada and T. Takahashi (2007)
Carcinogenesis 28, 2-12
   Abstract »    Full Text »    PDF »
MicroRNA promoter element discovery in Arabidopsis.
M. Megraw, V. Baev, V. Rusinov, S. T. Jensen, K. Kalantidis, and A. G. Hatzigeorgiou (2006)
RNA 12, 1612-1619
   Abstract »    Full Text »    PDF »
An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C. elegans.
R. J. Johnston Jr, J. W. Copeland, M. Fasnacht, J. F. Etchberger, J. Liu, B. Honig, and O. Hobert (2006)
Development 133, 3317-3328
   Abstract »    Full Text »    PDF »
Searching for Neuronal Left/Right Asymmetry: Genomewide Analysis of Nematode Receptor-Type Guanylyl Cyclases.
C. O. Ortiz, J. F. Etchberger, S. L. Posy, C. Frokjaer-Jensen, S. Lockery, B. Honig, and O. Hobert (2006)
Genetics 173, 131-149
   Abstract »    Full Text »    PDF »
The expanding transcriptome: the genome as the 'Book of Sand'.
L. M. Mendes Soares and J. Valcarcel (2006)
EMBO J. 25, 923-931
   Abstract »    Full Text »    PDF »
Architecture of a MicroRNA-controlled Gene Regulatory Network That Diversifies Neuronal Cell Fates.
O. HOBERT (2006)
Cold Spring Harb Symp Quant Biol 71, 181-188
   Abstract »    PDF »
The Expanding Universe of Noncoding RNAs.
Cold Spring Harb Symp Quant Biol 71, 551-564
   Abstract »    PDF »
A novel C. elegans zinc finger transcription factor, lsy-2, required for the cell type-specific expression of the lsy-6 microRNA.
R. J. Johnston Jr and O. Hobert (2005)
Development 132, 5451-5460
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882