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Science 309 (5737): 1078-1083

Copyright © 2005 by the American Association for the Advancement of Science

Formation of Regulatory Patterns During Signal Propagation in a Mammalian Cellular Network

Avi Ma'ayan,1 Sherry L. Jenkins,1 Susana Neves,1 Anthony Hasseldine,1 Elizabeth Grace,1 Benjamin Dubin-Thaler,3 Narat J. Eungdamrong,1 Gehzi Weng,1* Prahlad T. Ram,1{dagger} J. Jeremy Rice,4 Aaron Kershenbaum,4 Gustavo A. Stolovitzky,4 Robert D. Blitzer,1,2 Ravi Iyengar1{ddagger}

Abstract: We developed a model of 545 components (nodes) and 1259 interactions representing signaling pathways and cellular machines in the hippocampal CA1 neuron. Using graph theory methods, we analyzed ligand-induced signal flow through the system. Specification of input and output nodes allowed us to identify functional modules. Networking resulted in the emergence of regulatory motifs, such as positive and negative feedback and feedforward loops, that process information. Key regulators of plasticity were highly connected nodes required for the formation of regulatory motifs, indicating the potential importance of such motifs in determining cellular choices between homeostasis and plasticity.

1 Department of Pharmacology and Biological Chemistry Mount Sinai School of Medicine, New York, NY 10029, USA.
2 Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
3 Department of Biological Sciences, Columbia University, New York, NY 10029, USA.
4 Functional Genomics and Systems Biology, IBM T. J. Watson Research Center, Yorktown Heights, NY 10598, USA.

* Present address: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.

{dagger} Present address: Department of Molecular Therapeutics, M. D. Anderson Cancer Center, Houston, TX 77025, USA.

{ddagger} To whom correspondence should be addressed. E-mail: Ravi.Iyengar{at}

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