Fibroblast growth factor (FGF) signalling is critical for the initiation and regulation of multiple developmental processes including gastrulation, mesoderm induction and limb development. Despite extensive understanding of FGF signal transduction via tyrosine kinase receptors (RTKs), the specific mechanism responsible for regulation of target gene transcription is still not fully understood.
The protein Capicua (CIC) has been linked to transcriptional regulation in RTK signalling via the ERK pathway in multiple organisms. ERK signalling cascades also mediate wound signal transduction and transcription of associated genes. We hypothesise that transcription of a subset of FGF target genes, and genes involved in the wound response, rely on ERK mediated relief of CIC transcriptional repression.
The aims of this project were to establish if CIC operates downstream of FGF signalling through analysis and validation of RNA-seq data, and to investigate the relationship between CIC and ERK in FGF signalling and wound healing in Xenopus embryos.
The work in this thesis shows that CIC knockdown and FGF overexpressing embryos exhibit similar phenotypes and transcriptomes. Immunostaining for myc-tagged CIC indicates that CIC expression is reduced following activation of FGF signalling or the wound response. 75% of the putative CIC and FGF regulated genes analysed have enriched CIC binding sites and 75% were upregulated in RT-PCR analysis of CIC knockdown and FGF overexpressing embryos. Additionally, genes associated with wound healing (fos and gadd45a) are upregulated in CIC knockdown embryos. These data support the notion that CIC has a transcriptional regulatory role for a subset of FGF target genes and genes involved in the wound response.
Misregulation of the FGF signalling pathway and/or CIC repression is associated with a range of disorders and cancers. Consequently, understanding the molecular mechanisms involved in these pathways may allow development of more effective treatments for injury, neurodegenerative and developmental disorders, and cancer
