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Fig. 8. The signalling interactions that control dynamic regulation of gene
expression in the distal, digit-forming area of the limb bud. The scheme
depicts three distinct phases of limb bud morphogenesis in a simplified manner
(for details see text). Limb buds are drawn schematically with anterior
towards the top and posterior towards the bottom. Only genes relevant to the
present study are indicated. Phase I: setting up the signalling centres and
differential mesenchymal responsiveness. The expression of various key
regulator genes including Shh (dark blue), Grem1 (orange)
and 5'Hoxd genes (green) in the mesenchyme and FGF genes in the AER
(light blue) is activated locally and independent of SHH signalling. The
interaction of GLI3R with HAND2 and other transcription factors pre-pattern
the limb bud mesenchyme and regulate activation of their expression. Phase II:
SHH signalling (dark blue) and GREM1/FGF-mediated feedback signalling
(orange/light blue) are required to establish and propagate gene expression in
the distal limb bud mesenchyme. Epithelial-mesenchymal (EM) feedback
signalling regulates the temporally coordinated anterior expansion (yellow
arrow) of gene expression in the distal mesenchyme (Jag1 and
5'Hoxd genes) and FGF gene expression in the AER (light blue).
Jag1 becomes independent of SHH signalling early, while
5'Hoxd genes are progressively rendered SHH independent (with
3' to 5' polarity) as their presumptive digit expression domains
are being established. Phase III: the expanding population of Shh
descendants increasingly separates SHH signalling from GREM1 producing
mesenchymal cells, which probably causes breakdown of SHH/GREM1/FGF feedback
signalling and terminates limb bud patterning.
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