The gene regulatory Logic of Shh morphogen interpretation in the ventral neural tube.
Doctoral thesis, UCL (University College London).
During development, many signaling molecules function as morphogens, long-range signals, to provide positional information that directs the pattern of cellular differentiation. One such signal, Sonic Hedgehog (Shh), patterns the dorso-ventral (D/V) axis of the neural tube by controlling the expression of transcription factors in progenitor cells. One such factor is Nkx2.2, which is expressed in response to high levels and prolonged periods of Shh signaling. Analysis of the regulatory elements controlling Nkx2.2 has revealed a 250bp evolutionary conserved region (ECR), sufficient to drive Nkx2.2 expression. Among other transcription factor binding sites, this element contains a Gli‐binding site (GBS), necessary for Nkx2.2 expression. Mutational analysis suggests that the affinity and/or number of GBSs determine the level but not the spatial domain of Nkx2.2 expression pattern. Instead, correct Nkx2.2 expression requires both positive and negative inputs from other transcription factors. These factors are part of a transcriptional network that restricts Nkx2.2 expression in the p3 domain. One part of this network consisting of Pax6 and Olig2 determines the dorsal limit of Nkx2.2 expression, while a second part consisting of FoxA2, FoxP2 and FoxP4 determines the ventral limit of expression of Nkx2.2 domain. These transcription factors also appear to determine the temporal features of Nkx2.2 expression in the neural tube. Furthermore, sequence analysis identified a potential Fox binding motif within a 10bp region of the ECR that appears to control the ventral limit of Nkx2.2 expression. Together these data are consistent with a model in which the combination of Shh signaling and downstream transcriptional network generates the spatiotemporal profile of Nkx2.2 expression.
|Title:||The gene regulatory Logic of Shh morphogen interpretation in the ventral neural tube|
|Additional information:||Permission for digitisation not received|
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