Integration of signalling pathways in space and time is essential for normal patterning and growth of the vertebrate embryo. Despite this obvious statement, the genetic causes of congenital malformations have largely focused on monogenic changes, since gene-gene and gene-environment interactions are much more difficult to predict. While investigating the genetic networks controlling body axis elongation in vertebrates, we have uncovered a novel synergistic interaction between the retinoic acid (RA) pathway and miR-196, a family of micro-RNAs embedded within the Hox clusters. Inhibition of RA signalling using a pan-receptor antagonist (AGN193109) in utero led to radial aplasia, loss of digits, and split-hand phenotypes in miR-196 knockout (miR-196KO) animals. These malformations, reminiscent of Split-Hand-Foot Malformations (SHFM) seen in humans, were never observed in miR-196KO without RA inhibition, nor in wild-type animals upon the same AGN193109 treatment. To uncover the regulatory mechanisms accounting for this synergistic phenotype, we performed gene expression analysis of mouse wild-type and miR-196KO forelimb buds at E10.5, and performed in situ hybridization survey of genes and pathways involved in vertebrate limb development. Preliminary results show that Fgf8 and Shh expression is altered in miR-196 mutant limbs upon RA inhibition. This work has potential implication for the understanding of congenital malformations such as SHFM, in which a particular genetic makeup could sensitize the developing foetus to environmental insults.