Hedgehog signalling in zebrafish: Functional analysis of the pathway components. (360G-Wellcome-082962_Z_07_Z)

Exactly how Hh signalling is transduced and how it controls both cell fate specification and cell proliferation is still not well understood. Although the core components of the signal transduction pathway have been highly conserved during evolution, significant differences in the intracellular components exist between species. We aim to clarify the nature of this divergence in mechanisms and to elucidate the molecular interactions and processes that underlie the different outputs of Hh signalling. Specifically we will: 1) investigate the functional differences between the Hh receptors encoded by patched1 and patched2 and identify genes that link the Hh signal to growth in the zebrafish. 2) Use proteomic approaches to identify new components of the signalling pathway and characterise the interactions between known components. 3) Identify and characterise mutant alleles of genes encoding intracellular components of the pathway in the zebrafish and use double mutant analysis to elucidate their functional interactions. 4) perform chemical genetic screens to identify small molecule agonists and antagonists that act at different points in the pathway.