The dominant hemimelia mutation uncouples epithelial-mesenchymal interactions and disrupts anterior mesenchyme formation in mouse hindlimbs

Epithelial-mesenchymal interactions are essential for both limb outgrowth a nd pattern formation in the limb. Molecules capable of communication betwee n these two tissues are known and include the signaling molecules SHH and F GF4 FGF8 and FGF10. Evidence suggests that the pattern and maintenance of e xpression of these genes are dependent on a number of factors including reg ulatory loops between genes expressed in the AER and those in the underlyin g mesenchyme, We show here that the mouse mutation dominant hemimelia (Dh) alters the pattern of gene expression in the AER such that Fgf4, which is n ormally expressed in a posterior domain, and Fgf8, which is expressed throu ghout are expressed in anterior patterns. We show that maintenance of Shh e xpression in the posterior mesenchyme is not dependent on either expression of Fgf4 or normal levels of Fgf8 in the overlying AER, Conversely, AER exp ression of Fgf4 is not directly dependent on Shh expression. Also the recip rocal regulatory loop proposed for Fgf8 in the AER and Fgf10 in the underly ing mesenchyme is also uncoupled by this mutation, Early during the process of limb initiation, Dh is involved in regulating the width of the limb bud , the mutation resulting in selective loss of anterior mesenchyme, The Dh g ene functions in the initial stages of limb development and we suggest that these initial roles are linked to mechanisms that pattern gene expression in the AER.