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Fig. 7. Summary of paracrine interactions and a model for a degenerative cycle
that could explain the local variation of phenotype in Foxf mutant
intestine. In wild type, both Foxf genes are activated in mesenchymal
cells by hedgehog produced by the epithelium. Cell-autonomous stimulation of
ECM production is more dependent on Foxf2 than on Foxf1, whereas both proteins
activate Bmp4. Bmp4 inhibits Wnt5a expression in the
mesenchyme and there may also be other mechanisms (`?') through which Foxf
proteins restrict Wnt5a. The ECM provides tight contact between
epithelium and mesenchyme, induces epithelial polarity and ensures efficient
signaling of both Hh and Wnt ligands. The loss of both Foxf2 alleles
will result in reduced Bmp4 and increased Wnt5a expression,
but foremost in a radical decrease of several ECM components. The ECM
deficiency will lead to loss of epithelial polarity, but not to apoptosis at
this stage because of the stabilized ß-catenin that results from
increased Wnt signaling. However, the poor adhesion, particularly between
epithelium and the weakened basement membrane, creates an unstable situation
where even moderate physical strain (e.g. from peristalsis) will separate the
epithelium from the mesenchyme. Once parted, mesenchymal cells will experience
a reduced Hh signaling, expression from the remaining Foxf alleles (in this
example the two Foxf1 alleles) will drop and the phenotype
deteriorates further. When ECM production falls below a certain level, the
tissue disintegrates and epithelial cells end up too far from the source of
Wnt5a to be rescued from apoptosis. Foxf1-/+;
Foxf2-/+ compound heterozygotes initially have a less
dramatic reduction in ECM, which sustains tissue integrity longer and supports
more efficient epithelio-mesenchymal signaling, allowing the epithelium to
overgrow. Given the reduced Foxf gene dose and weakened basement membranes,
the tissue is, however, vulnerable to the same degenerative cycle, which may
be the cause of the observed low-ß-catenin/apoptosis mosaic pattern.
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