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PLoS Comput Biol. 2014 Feb 13;10(2):e1003463. doi: 10.1371/journal.pcbi.1003463. eCollection 2014.

A BMP-FGF morphogen toggle switch drives the ultrasensitive expression of multiple genes in the developing forebrain.

Author information

  • 1Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America ; Center for Complex Biological Systems, University of California, Irvine, California, United States of America ; Department of Computer Science, University of California, Irvine, California, United States of America.
  • 2Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.
  • 3Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America ; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • 4Department of Pathology and Laboratory Medicine, University of California, Irvine, California, United States of America.
  • 5Department of Computer Science, University of California, Irvine, California, United States of America.
  • 6Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America ; Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
  • 7Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America ; Center for Complex Biological Systems, University of California, Irvine, California, United States of America ; Department of Pathology and Laboratory Medicine, University of California, Irvine, California, United States of America.

Abstract

Borders are important as they demarcate developing tissue into distinct functional units. A key challenge is the discovery of mechanisms that can convert morphogen gradients into tissue borders. While mechanisms that produce ultrasensitive cellular responses provide a solution, how extracellular morphogens drive such mechanisms remains poorly understood. Here, we show how Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) pathways interact to generate ultrasensitivity and borders in the dorsal telencephalon. BMP and FGF signaling manipulations in explants produced border defects suggestive of cross inhibition within single cells, which was confirmed in dissociated cultures. Using mathematical modeling, we designed experiments that ruled out alternative cross inhibition mechanisms and identified a cross-inhibitory positive feedback (CIPF) mechanism, or "toggle switch", which acts upstream of transcriptional targets in dorsal telencephalic cells. CIPF explained several cellular phenomena important for border formation such as threshold tuning, ultrasensitivity, and hysteresis. CIPF explicitly links graded morphogen signaling in the telencephalon to switch-like cellular responses and has the ability to form multiple borders and scale pattern to size. These benefits may apply to other developmental systems.

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