Genetic interactions suggest that Danforth's short tail (Sd) is a gain-of-function mutation

Danforth's short tail (Sd) is a semidominant mutation on mouse chromosome 2 that acts cell autonomously in the notochord and leads to its disintegration, and thus causes severe defects in somite patterning and vertebral column development. The molecular nature of the Sd gene and mutation is unknown, and it is unclear whether Sd is a loss-of-function mutation and the semidominant inheritance of the Sd phenotype is due to haploinsufficiency, or whether Sd represents a gain-of-function mutation in a gene essential for notochord development and maintenance. Here, we report on the genetic interaction between Sd and an insertional mutation called Etl4^lacZ, which provides genetic evidence that Sd is a gain-of-function mutation. Etl4^lacZ is an enhancer trap insertion, which gives rise to lacZ expression in distinct cell types, including the notochord. In homozygosity, the lacZ insertion leads to abnormal vertebrae in the caudal part of the vertebral column. Etl4^lacZ maps approximately 0.75 cM distal to Sd, and in double heterozygotes modifies the Sdphenotype contrarily, depending on the chromosomal configuration of the Sd and Etl4^lacZ mutations: when Etl4^lacZ is present on the chromosome wild type for Sd (Sd +/+ Etl4^lacZ; trans configuration), the Sd phenotype is enhanced, i.e., vertebral malformations extend to more anterior positions and the vertebral body of the axis is further reduced. Conversely, when Etl4^lacZ is present on the same chromosome as Sd (Sd Etl4^lacZ /+ +; cis configuration), the Sd phenotype is attenuated, i.e., vertebral malformations are confined to more posterior levels, and the dens axis, which is severely reduced or absent in Sd heterozygotes, is restored. The different effect of the Etl4^lacZ insertion on Sd, depending on its presence in trans or cis, suggests a direct interaction of the transgene insertion with the Sd gene. Additionally, the attenuation of the Sd phenotype by Etl4^lacZ in cis suggests that Sd is a gain-of-function mutation and lends support to the idea that Etl4^lacZ is a new allele of Sd. Dev. Genet. 23:86–96, 1998. © 1998 Wiley-Liss, Inc.