Mutations in a conserved non-coding region in intron 5 of the Lmbr1 locus, which 
is 1 Mb away from the sonic hedgehog (Shh) coding sequence, are responsible for 
mouse and human preaxial polydactyly with mirror-image digit duplications. In 
the mouse mutants, ectopic Shh expression is observed in the anterior mesenchyme 
of limb buds. Furthermore, a transgenic reporter gene flanked with this 
conserved non-coding region shows normal polarized expression in mouse limb 
buds. This conserved sequence has therefore been proposed to act as a 
long-range, cis-acting regulator of limb-specific Shh expression. Previous 
phylogenetic studies have also shown that this sequence is highly conserved 
among tetrapods, and even in teleost fishes. Paired fins of teleost fishes and 
tetrapod limbs have evolved from common ancestral appendages, and polarized Shh 
expression is commonly observed in fins. In this study, we first show that this 
conserved sequence motif is also physically linked to the Shh coding sequence in 
a teleost fish, the medaka, by homology search of a newly available genomic 
sequence database. Next, we show that deletion of this conserved intronic 
sequence by targeted mutation in the mouse results in a complete loss of Shh 
expression in the limb bud and degeneration of skeletal elements distal to the 
stylopod/zygopod junction. This sequence contains a major limb-specific Shh 
enhancer that is necessary for distal limb development. These results suggest 
that the conserved intronic sequence evolved in a common ancestor of fishes and 
tetrapods to control fin and limb development.