Regulation of planar cell polarity signalling by the prenylation pathway

During vertebrate gastrulation, the body axis is established by a variety of co-ordinated and directed movements of cells. One of these movements is convergence and extension (CE), which is regulated by a non-canonical Wnt/planar cell polarity (PCP) pathway. From our forward genetic screen, we have identified 3-hydroxy-3-methyglutaryl-coenzyme A reductase 1b (hmgcr1b) gene as a dominant enhancer of the silberblick (slb)/wnt11 CE phenotype. hmgcr1b mutant embryos exhibit only very mild CE phenotype during gastrulation while showing a thicker yolk extension at pharyngula stages. Notably, abrogation of hmgcr1b also enhances the CE defects of other core PCP mutants/morphants. The prenylation pathway is one of branches downstream of HMGCR, and has been implicated for lipid modification at the C-terminus of proteins. To test the possibility that the prenylation pathway regulates activities of the PCP pathway, we abrogated farnesyl transferase (FT) or geranylgeranyl transferase (GGT) function using morpholinos on PCP mutant/morphant backgrounds. Consistent with the notion that FT preferentially performs lipid modification on to proteins with the CAAX motif including the core PCP protein Prickle (Pk), abrogation of FT, but not GGT, enhances the pk1a or pk1b morphant CE phenotype, suggesting the specif icity for targets of the prenylation enzymes.