Esteves Ribeiro, A.C.;
Shh signalling and the dynamic patterning of the vertebrate
Doctoral thesis, UCL (University College London).
Restricted to Access restricted until 1 March 2016.
The formation of the central nervous system depends on the patterned generation of different neuronal and glial cell types during embryogenesis. In ventral regions of the neural tube, the graded activity of the secreted molecule Sonic Hedgehog (Shh) controls the position along the dorsoventral axis at which different neuronal subtypes differentiate. Here, using chick and mouse embryos, we systematically and quantitatively documented the spatial and temporal expression patterns of the transcription factors that delineate the progenitor domains of these neurons. We investigated the coordination of the patterning activity of Shh with tissue growth and cell differentiation and discovered a high degree of conservation in pattern formation between mouse and chick. In addition, quanti"cation of the levels of Shh protein in vivo and downstream signalling activity using a mouse reporter of Gli activity con"rmed the non-linear relation between ligand concentration, levels of intracellular signalling and expression of the target genes in vivo. These data support a model in which progenitor cells respond to the cumulative amount of Gli activity. To advance our understanding of how cells transduce the Shh signal we investigated the vertebrate orthologs of Costal2, a component of the Hedgehog pathway in Drosophila. Using a gain of function assays in chick we con"rmed that one of the orthologs, the kinesin Kif7, is a negative regulator of the Shh signalling pathway, acting downstream of Smoothened. The inhibitory activity of Kif7 required only the N-terminal region containing the motor domain. By contrast, the kinesin Kif27, which appears equally similar to Costal2 as Kif7, was unable to inhibit Shh signalling. These data provided evidence that Kif7 was a novel component of the vertebrate Hh signalling and revealed a greater conservation between the Drosophila and vertebrate system than previous views suggested.
|Title:||Shh signalling and the dynamic patterning of the vertebrate neural tube|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology|
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