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Fig. 2. Restoration of GREM1/FGF mediated EM feedback signalling in Grem1^In2/In2 limb buds rapidly rescues expression of Shh, Jag1 and Hoxd13 in the distal mesenchyme. Cell aggregates producing either gremlin 1 (GREM1, green circles) or FGF4 (FGF4, blue circles) were grafted into the posterior mesenchyme of Grem1^In2/In2 forelimb buds (E10.25, 31-33 somites). In these studies, the grafts were placed more distally and further away from the posterior AER than in previous experiments in order to avoid disruption of the posterior mesenchyme competent to express Shh. Circles indicate the approximate size and positions of the grafts after culturing, coloured arrowheads indicate induced/upregulated gene expression. White arrowheads indicate endogenous gene expression in contralateral control limb buds. (A) GREM1 rescues Shh expression (red arrowhead) within 9 hours, indicative of restored EM feedback signalling. (B) GREM1 induces Fgf4 expression (arrowhead) in the posterior AER within 9 hours. (C) Grafts of FGF4-expressing cells in turn upregulate the expression of Shh within 9 hours (red arrowhead). (D,E) GREM1 upregulates the expression of the SHH targets Jag1 (D; blue arrowhead) and Hoxd13 (E; pink arrowhead) in the distal mesenchyme within 15 hours. (F,G) FGF4 also induces the upregulation of Jag1 (F; blue arrowhead) and Hoxd13 expression (G; pink arrowhead) in the distal mesenchyme of Grem1-deficient limb buds within 15 hours.

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