18-P002 A Sonic Hedgehog controlled gene network in the neural tube acts as a multistate switch to generate progenitors of distinct neuronal subtypes

Abstract

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.