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Title: A novel role for complement factor C9 on canonical Wnt/β-catenin signaling and neural crest induction
Author: Melchionda, M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The neural crest is a multipotent and highly migratory embryonic cell population induced at the border between the neural plate and the prospective epidermis by a combination of Wnt, BMP, FGF and Retinoic acid signaling pathways. In an attempt to find novel candidate molecules involved in neural crest development we focused our attention on complement factor C9 (C9), a key members of the complement system well known for its role in innate and adaptive immunity. At present, there is no evidence for a role of C9 in early embryo development. Using a combination of reverse transcriptase-PCR and in situ hybridization analysis, we found that C9 is expressed in the ectoderm of late Xenopus blastula and the prospective neural crest domain and surrounding tissues of gastrula embryos. Additionally, C9 is present in the NC and adjacent regions in neurula and tailbud stages Xenopus embryos. Loss-of-function studies in vivo and in vitro show that C9 is required in the ectoderm and the neural crest to initiate NC induction. Furthermore, it appears that C9 activity is strongly required during neural plate border formation and moderately needed for the maintenance of the newly specified neural crest precursors. Beads soaked with a C9 blocking antibody lead to a strong inhibition of neural crest induction when grafted during neural plate border specification than during mid-neurula stages. By performing tissue recombination experiments and luciferase-based assay to measure β-catenin activity, I demonstrate that morpholino and antibody-mediated knockdown of C9 strongly reduces canonical Wnt signaling. Additionally, I show that C9 can affect Wnt-mediated activity such as dorsal axis formation and anterior-posterior patterning. Finally, I show that complement factor C3 and C7 are also required for proper NC formation and affect Wnt-mediated activity, thus indicating that C9 functions via the complement cascade to regulate neural crest formation through the positive modulation of the Wnt/β-catenin signaling pathway. In conclusion, my results are in support of a novel functional role for complement factor C9 in regulating neural crest induction through the positive modulation of the canonical Wnt/β-catenin signaling pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available