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PNAS 102 (35): 12449-12454

Copyright © 2005 by the National Academy of Sciences.

From the Cover


DEVELOPMENTAL BIOLOGY

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}columbia.edu.

© 2005 by The National Academy of Sciences of the USA


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