Cox, Barnaby Thomas Montgomery; (1999) The role of a novel FAT-like cadherin in mouse development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Members of the cadherin superfamily play roles in calcium-dependent cellular recognition and adhesion events, in regulated integration and segregation of heterogenous cell populations, and in formation of the organised cellular pattern of tissues and organs of multicellular organisms. More recent evidence suggests a dual role for these molecules in both adhesion and signalling. One 'cadherin-related' locus, Drosophila fat, encodes an enormous transmembrane protein of over five thousand amino acids, containing an extracellular domain with 34 tandem cadherin repeats, and a cytoplasmic domain containing conserved regions required for catenin binding. Recessive lethal mutations of fat cause hyperplastic tumour-like outgrowths of fly imaginal discs in a cell-autonomous fashion, defects in differentiation and morphogenesis, and death at the pupal stage, indicative of fat playing a role in the control of cell proliferation, and acting as a tumour suppressor gene. The cloning of the human homologue of fat (FAT) shows that this gene is conserved between vertebrates and invertebrates. Further studies, using a novel gene trap technique, the secretory trap, has identified clones of a mouse fat homologue (mfat1). The whole mfat1 open reading frame of over 15kb has been cloned and its sequence is reported here. I have shown, using RT-PCR, that mfat1 expression is initiated at the eight cell stage, and is ubiquitous in the adult. A specific mfat1 expression pattern is seen within 7.5-11.5 d.p.c. whole embryos in brain, somites and limb buds and is restricted to highly proliferative areas of the 12.5-16.5 d.p.c. brain as well as the otic vesicle, the optic vesicle and the vibrissa follicle primordia. Anti-Fat peptide and recombinant protein antisera have been raised and detect mFat1 antigen generated in a bacterial expression system; they have been used to detect mFat1 endogenous protein using western blotting. These antibodies can be used to address a possible role of Fat in cell proliferation and/or differentiation, and its interactions with other proteins.

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