title: A BMP-FGF morphogen toggle switch drives the ultrasensitive expression of multiple genes in the developing forebrain.
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.
authors.affiliation: Department 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.
authors.forename: Shyam
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.
authors.forename: Jia Sheng
authors.initials: JS
authors.lastname: Hu
authors.affiliation: Department 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.
authors.forename: D Spencer
authors.initials: DS
authors.lastname: Currle
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, California, United States of America.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Fung
authors.affiliation: Department of Computer Science, University of California, Irvine, California, United States of America.
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Hayes
authors.affiliation: Department 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.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
authors.affiliation: Department 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.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D019295:Computational Biology; D046149:Embryo Culture Techniques; D025461:Feedback, Physiological; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051957:MSX1 Transcription Factor / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011247:Pregnancy; D016548:Prosencephalon / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013687:Telencephalon / Q000187:drug effects / Q000196:embryology / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors