2 INDEPENDENT AND INTERACTIVE DNA-BINDING SUBDOMAINS OF THE PAX6 PAIRED DOMAIN ARE REGULATED BY ALTERNATIVE SPLICING

Vertebrate Pax proteins share a conserved 128-amino-acid DNA-binding m otif, the paired domain. The PAX6 gene, which is mutated in the murine Small eye and human aniridia developmental defects, also encodes a se cond protein with a 14-amino-acid insertion in the paired domain. This protein, which arises by alternative mRNA splicing, exhibits unique D NA-binding properties. Unlike other paired domains, which bind DNA pre dominantly by their amino termini, the extended Pax6 paired domain int eracts with DNA exclusively through its carboxyl terminus. This proper ty can be simulated by deletion of 30 amino-terminal residues from the Pax6 or Pax2 paired domains. Thus, the insertion acts as a molecular toggle to unmask the DNA-binding potential of the carboxyl terminus. T he functional nonequivalence of the two Pax6 proteins is underscored b y a T --> C mutation at position -3 of the alternative splice acceptor site that changes the ratio of the two isoforms and causes a distinct human ocular syndrome.