SHH, FGF4 AND HOXD GENE-EXPRESSION IN THE MOUSE LIMB MUTANT HYPODACTYLY

The semidominant mouse mutation hypodactyly (Hd), caused by a deletion within the Hoxa 13 gene, results in reduced digits; heterozygotes lac k digit I in the hindlimb and homozygotes have only one digit on each limb. We investigated expression of Shh and Fgf4 signaling molecules i nvolved in digit specification in mutant limb buds. Shh and Fgf4 are e xpressed in the posterior part of the limb buds as normal but expressi on may be slightly prolonged. The extent of digit reduction in hypodac tyly is much more severe than in the Hoxa 13 deficient mouse and resem bles that in the Hoxa13(-/-)/Hoxd13(-/-) double mutant mouse. We found that the pattern of Hoxd13 and Hoxd11 transcripts was not markedly di fferent in the mutant compared with the normal limbs even though the m utant limbs are narrower. Therefore Hoxd genes are transcribed as norm al in the muta nt. Th is makes it likely that the severe digit reducti ons in hypodactyly are caused by interference with Hoxd13 function at the protein level. Similar interactions between mutant and normal HOX gene products have been suggested to occur in the human semidominant d isorder, synpolydactyly, caused by mutations in HOXD13.