Dissecting complex genetic interactions that influence the Engrailed-1 limb phenotype.

Engrailed-1, a homeobox containing transcriptional repressor, is known to play an important role in the development of the vertebrate limb. In its absence, mouse limbs develop with improper specification of dorsal identity and digit abnormalities. We report here that specific malformations in the mutant limb are dependent on strain background. We have subdivided these defects on the basis of morphology to define five independent traits. Each of these shows marked differences in prevalence among the 129/S1 and C57BL/6J strains carrying the En1(hd) mutation. In a genome-wide scan using SSLP markers, we have determined the location of one significant modifier and several additional suggestive loci responsible for these traits, each a facet of the En1(-/-) phenotype. We propose this type of sensitized genetic screen as a model approach for the discovery and mapping of quantitative loci that affect the subtle details of limb pattern formation.