TARGETED DISRUPTION OF PAX1 DEFINES ITS NULL PHENOTYPE AND PROVES HAPLOINSUFFICIENCY

The murine paired box-containing gene Pax1 is required for normal deve lopment of the vertebral column, the sternum, and the scapula, Previou s studies have shown that three natural Pax1 mouse mutants, the undula ted alleles, exhibit phenotypes of different severity in these skeleta l elements. Nevertheless, these analyses have not clarified whether th e semidominant Undulated short-tail (Un(s)) mutation, in which the com plete Pax1 locus is deleted, represents a null allele. Moreover, the a nalyses of the classical undulated mutants did not allow a conclusion with respect to haploin-sufficiency of Pax1. To address both questions we have created a Pax1 null allele in mice by gene targeting. Surpris ingly, the phenotype of this defined mutation exhibits clear differenc es to that of Un(s). This result strongly indicates the contribution o f additional gene(s) to the Un(s) mutant phenotype. Furthermore, the p henotype of mice heterozygous for the null allele demonstrates that Pa ul is haploinsufficient in some though not all skeletal elements which express Pax1 during embryonic development.