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.
Highlights
The formation of borders between compartments and body parts is crucial for embryonic development [1,2,3,4,5]
We show how a cross-inhibitory positive feedback or toggle switch mechanism driven by two extracellular morphogens – Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) - produces ultrasensitivity in forebrain cells
By an iterative combination of modeling and experiment, we show the toggle switch to be the mechanism underlying cross inhibition, the ultrasensitive expression of multiple genes, and hysteresis in forebrain cells
Summary
The formation of borders between compartments and body parts is crucial for embryonic development [1,2,3,4,5]. Extensive studies in many systems [6], including the mammalian spinal cord [8] and syncytial fly blastoderm [6,9], show that ultrasensitivity and border formation can result from complex interactions between a morphogen and its downstream transcription factor network, or within a transcriptional network alone. While such morphogen-transcription networks have been explored, the interactions between extracellular morphogens as a basis for ultrasensitivity has not been described, even though such interactions are common in development [10]
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