DECK 4: Case Study 2 - ZRS/SHH (Preaxial Polydactyly & Serpentized Mice)

To master the ZRS story, which is unique because it covers both disease and evolution - this makes it ideal for integrative questions.

What gene does the ZRS enhancer regulate?

SHH (Sonic Hedgehog)

What does ZRS stand for?

Zone of Polarizing Activity Regulatory Sequence

How far is ZRS from SHH?

1 Mb upstream

What phenotype results from SNVs in ZRS?

Preaxial Polydactyly (extra digits)

How do SNVs in ZRS cause polydactyly?

Cause ectopic SHH expression on the anterior limb bud

What evolutionary insight came from ZRS studies?

Snake-specific loss of function in the limb enhancer

What specific TF motif was lost in snakes?

ETS1 motif

What happened when mouse ZRS was replaced with snake ZRS?

Severe limb reduction ("serpentized" mice)

What happened when the ETS1 motif was synthetically restored?

Full enhancer function was restored

What does this demonstrate about morphological evolution?

Single regulatory sequence changes can drive major body plan transitions

What assay showed ZRS function across species?

Transgenic mouse reporter assays

Which species has the conserved ZRS enhancer activity pattern?

Vertebrates including fish, but NOT snakes

What happens when the mouse enhancer is replaced with human or fish ortholog?

Normal limb development