Kenyon, E.J.; (2007) Investigations into the Rab family of genes and their roles in signalling during vertebrate early development. Doctoral thesis , University of London.

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Abstract

The mammalian Rab family consists of between 60-70 members, making it the largest sub family of the Ras superfamily. Rabs are responsible for vesicle trafficking within cells, acting as molecular switches cycling between the GDP inactive and GTP bound active forms. Far from being just cellular housekeeping genes, these genes have been shown to have specific functions which, when disrupted, can lead to clinical disorders and interesting developmental defects. This thesis therefore seeks to investigate this interesting family of genes and their roles in zebrafish development. Using antisense morpholino oligonuleotides in a loss of function screen, this thesis identifies the function of 13 zebrafish rabs. Three of these, rabla3, rab3cl and rab28 have specific and interesting phenotypes, with pigmentation defects seen in rabla3 and rab3cl and behavioural defects seen in rab28. In particular, the pigmentation defect in rab3cl resulted in the discovery that the embryos were blind. This thesis also shows an essential role for rab5a2 in zebrafish development and Nodal signalling. Disruption of this rab causes a dramatic early phenotype, with 100% mortality in embryos prior to 24 hours post fertilization. rab5a2 morpholino injected embryos show no visable organizer and have reduced nodal target gene expression. Overexpression of rab5a2 shows embryos with additional expression of Nodal target genes no tail and goosecoid in the animal pole of the embryos but not the dorsal marker chd. Microarray analysis of rab5a2 morpholino injected embryos showed reduction and upregulation of expression of many genes involved in dorsal ventral patterning. This suggests a complex role for rab5a2 in patterning the early embryo, as both dorsalizing and ventralizing genes such as chd, bmp4 and wnt8 were down regulated while, ventralizing genes such as bmp2b were upregulated.

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