SummarySecreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.
The secreted protein Hedgehog (Hh) acts a morphogen, forming a concentration gradient and controlling cell fate decisions in various developmental stages in many animals. In recent years, there has been significant interest in the role that glypicans play in Hh gradient formation and signalling; with various experimental studies demonstrating an effect on Hh transport, Hh stability and downstream transcription factor (CI) activity.Using mathematical modelling and analysis, we investigate the effects glypicans (e.g. Dally, Dlp) have on gradient formation and target gene expression domains. The incorporation of Hhglypican complexes yields models whose behaviour matches current experimental data more accurately than previous models. Furthermore, we show that interaction with glypicans enhances the robustness of 1. Hh levels at the Anterior-Posterior compartment boundary, 2. the position of expression boundaries of target genes, to variations in Hh production and wing disc size (after certain critical thresholds).We show that enhanced model robustness is affected by (a) restriction of the amount of glypican available to Posterior compartment cells, (b) reduction of the degradation rate of Hh-glypican complex (relative to 'free' Hh) and (c) making the rate of morphogen transport dependent on the amount of free glypican.
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