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