Shh Signalling and the Specification of Neuronal Identity

Stamataki, Despina (2005). Shh Signalling and the Specification of Neuronal Identity. PhD thesis The Open University.



During development, many signalling factors behave as morphogens, long-range signals eliciting different cellular responses according to their concentration. In ventral regions of the spinal cord, Shh is such a signal and controls the emergence, in precise spatial order, of distinct neuronal subtypes. The Gli family of transcription factors play a central role in this process, however, how the graded aspect of Shh signalling controls differential gene expression has been unclear. To address this question we have taken a gain of function approach in chick embryos. We have designed dominant inhibitory and dominant active versions of Gli proteins that are sufficient to block all Gli mediated transcription or mimic positive Gli activity, respectively. Analysis of the effect of these constructs when ectopically expressed in chick embryonic spinal cord indicates that blocking Gli mediated transcription prevents ventral neural tube patterning and the generation of the appropriate neuronal subtypes resulting in the dorsalisation of the ventral neural tube. Conversely, Gli dependent transcription is sufficient to mediate the full range of Shh responses in the neural tube. Moreover, the 2-3 fold changes in Shh concentration, which are necessary to switch between alternative neuronal subtypes in vitro, can be mimicked in vivo by similarly small changes in the level of Gli activity. This analysis also indicated that cells integrate the level of Shh signalling over time suggesting that signal duration in addition to signal strength is an important parameter controlling dorsal-ventral patterning. Together, these data indicate that graded Shh signalling is translated into a gradient of Gli activity without substantial signal amplification and that small changes in the level of Gli activity are sufficient to orchestrate the patterning of the ventral neural tube.

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