In many developing tissues, gradients of extracellular signalling molecules – often termed morphogens – act as patterning cues by dividing the tissue into a series of molecularly distinct territories. This is the case in the ventral neural tube where a gradient of Shh signalling divides neural progenitors into a series of domains arrayed along the dorsal-ventral axis. Most models of morphogen interpretation are based on the idea that thresholds of morphogen concentration determine cell identity. In this view, increasing concentrations of morphogen generate increasing levels of intracellular signalling with the result that distinct target genes are activated at different levels of signalling. However, we found that the duration, as well as the level, of Shh signalling is important for morphogen interpretation in the neural tube. This has led to a revision of the morphogen concept in which the dynamics of the morphogen drive patterning. We hypothesize that the wiring of the intracellular transduction pathway generates temporal adaptation. To investigate this we are developing reagents that provide quantitative, dynamic measures of pathway activity. High resolution, quantitative data of the kinetics of Shh signalling in the neural tube are the starting point for testable dynamical systems models of Shh signal transduction

Developmental noise and spatiotemporal precision

The precision of the Shh morphogen gradient does not appear sufficient to explain the precision of developmental patterning. However the mechanisms that reinforce patterning and filter noise in gradient formation, morphogen signalling, and target gene expression are poorly understood. To measure spatial and temporal fluctuations in Shh pathway activity, we are using reporters that monitor the activity of Gli proteins, the transcriptional effectors of Shh signalling. The downstream gene regulatory network (GRN) may buffer the effects of signalling noise and fluctuations in morphogen concentration. This provides a means to filter and temporally average signal input that would buffer temporal fluctuations in morphogen signalling. To test this we are developing reporters for targets of Shh signalling in the ventral neural tube. These will provide measurements of cell-to-cell variability in Shh signalling and transcriptional responses. Based on these data, we are developing mathematical models of the conversion of the Shh signalling activity into gene regulation and the influence of noise on this process.

SELECTED PUBLICATIONS

  • Cohen, M; Kicheva, A; Ribeiro, A; Blassberg, R; Page, KM; Barnes, CP and Briscoe, J (2015)
    Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms.
    Nature Communications 6, 6709 PubMed abstract
  • Cohen, M; Briscoe, J and Blassberg, R (2013)
    Morphogen interpretation: the transcriptional logic of neural tube patterning.
    Current Opinion in Genetics & Development 23, 423-428 PubMed abstract
  • Balaskas, N; Ribeiro, A; Panovska, J; Dessaud, E; Sasai, N; Page, Karen M; Briscoe, J and Ribes, V (2012)
    Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube.
    Cell 148, 273-284 PubMed abstract