Q J Med 2002; 95: 487-488
© 2002 Association of Physicians
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Flies in the colon
Any regular reader of this column will have noticed a preoccupation with developmental pathology. This is a personal interest, but depends on a conviction that the mechanisms of development, properly understood, are central to the development of most degenerative disease and of much other pathology. The latest surprise is about carcinoma of the colon.
The Adenomatous Polyposis Coli (APC) tumour suppressor gene is known to be affected in many families who have a high incidence of carcinoma of the colon and to show truncation mutations in about 80% of colonic adenomas and carcinomas in sporadic cases. The tumour suppressor function of the gene depends on its ability to promote the degradation of ß-catenin, a protein that functions in intercellular junctions in epithelium. What has this to do with wingless fruit flies?
It's all to do with the Wnt family of genes. These genes are probably the oldest group of signalling molecules in the animal kingdom. The name comes from a fusion of the Drosophila segment polarity gene wingless with the name of one of its vertebrate homologues, integrated (Wingless/Integrated). Wnt-derived glycoproteins are found in all animals from hydra to insects, worms and vertebrates. There are 19 genes in humans (and 17 in the mouse). The surface receptors for Wnt proteins are members of the Frizzled transmembrane receptor family, of which there are at least ten in Man. These receptors produce their intracellular effects via the Dishevelled protein, which inhibits the phosphorylation and subsequent destruction of ß-catenin by cell mechanisms. Thus in the absence of Wnt signalling, ß-catenin is rapidly destroyed. ß-catenin normally acts as a link between the cytoskeleton and the extracellular matrix, downstream of the calcium-dependent cadherins. Stabilized (non-phosphorylated) ß-catenin is translocated into the nucleus, where it induces transcription of c-myc and Cyclin D and thus affects cell proliferation. This ancient signalling pathway plays a role in determining polarity in the embryo and in renal and skeletal development; signalling via ß-catenin also initiates vertebrate limb development.1
So, in general, the accumulation of ß-catenin is likely to produce proliferation and to inhibit differentiation. The phenotypes associated with abnormalities of the APC genes are curiously restricted, to the gastric, small and large bowel epithelia, to bone (osteoma), mesenchyme (desmoid fibromatosis) and lesions in the retina and pigment epithelium of the eye. There are many other sites of expression of the gene, and the mutations found in colonic carcinoma have been found in tumours that are not seen in APC families. The answer(s) may lie in the multiple (and separately evolved) methods by which signalling occurs.
The early response to Wnt signalling in vertebrates is a dorsalizing one that establishes the dorso-ventral axis. Later, however, the same signal patterns the ventral mesoderm; how is this inversion of function brought about? Both functions depend on ß-catenin activity, so does the nuclear response determine the different cellular responses? In fact, it's not that simple.
The planar cell polarity pathway (PCP)2 works in Drosophila to ensure that all the cuticular cells produce hairs that point in the same direction. The same mechanism ensures the proper formation of the primary germ layers in humans: during gastrulation, migrating cells are polarized by the PCP and extrude lammelipodia along one axis only, ensuring proper orientation of ectoderm, mesoderm and endoderm via interactions with the cytoskeleton. This pathway uses Dishevelled but not ß-catenin; the effector is Cdc-42, a GTP-binding protein.
There is a third pathway. Slusarski et al.3 found that Wnt5a together with Frizzled-2 mobilizes Ca++ ions, thus activating Ca++-dependent enzymes and affecting cell adhesion.4 These authors were able to disrupt gastrulation using antisense oligonucleotides for the Frizzled-7 receptor, resulting in failure of mesodermal/ectodermal separation.
It seems that it is the particular Wnt/Frizzled combination that determines which of the three pathways is used and thus confers specificity on any particular developmental effect (see also reference 5). In one gene/receptor family we thus have actions that affect all aspects of development and neoplasia; cell proliferation rates, cell cycle times, cell (and tissue) polarity and cell/cell/stroma adhesion.
How clever.
References
1. Martin G. Making a vertebrate limb: new players enter from the wings. Bioessays2001; 23:865–8.[Web of Science][Medline]
2. Mlodzik M. Planar polarity in the Drosophila eye: a multifaceted view of signaling specificity and cross-talk. EMBO J1999; 18:6873–9.[Web of Science][Medline]
3. Slusarski DC, Yang-Snyder J, et al. Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A. Dev Biol1997; 182:114–20.[Web of Science][Medline]
4. Winklbauer R, Medina A, et al. Frizzled-7 signalling controls tissue separation during Xenopusgastrulation. Nature2001; 413:856–60.[Medline]
5. Boutros M, Mlodzik M. Dishevelled: at the crossroads of divergent intracellular signaling pathways. Mech Dev1999; 83:27–37.[Web of Science][Medline]
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