Final Activity Report Summary - SPLICING (Splice variants as modifiers of the Patched-Hedgehog signalling pathway) During these two years, I investigated the functional significance of splice variants involved in hedgehog (HH) signalling pathway. In the first project step, I performed in-silico screening to identify splice variants in the HH signalling components. Based on the results from several databases, I found 39 putative alternative splicing variants from 14 genes which were HH signalling components. These candidates were placed in a priorities' order based on novelty and putative function. Among these candidates, I focused on the variations of both the tumour suppressor gene, patched 1 (PTCH1), and the oncogene, glioma-associated oncogene 1 (GLI1). During the PTCH1 variants analysis, we identified a novel first exon and demonstrated the unique biological properties of the PTCH1 isoforms which were generated by alternative first exon usage. This finding was published in 'Oncogene' (vol. 27, pages 4889-4896, 2007). In this article, we proposed the dynamic regulation of HH signalling by PTCH1 variants. As part of the GLI1 variants' analysis, we identified a novel human GLI1 variant, which was generated by skipping exons 2 and 3 and encoding an N-terminal truncated GLI1 protein. We examined the functional properties of GLI1 splice variants, including its transcriptional regulation, activity and cellular localisation. This finding was published in 'J. Biol. Chem.' (online on March 31, 2008). In addition, we also identified mouse GLI1 variants and investigated their regulation and roles in HH signalling (manuscript, 2008).