The mouseUlnalessmutation deregulates posteriorHoxDgene expression and alters appendicular patterning

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Abstract
The semi-dominant mouse mutation Ulnaless alters patterning of the appendicular but not the axial skeleton. Ulnaless forelimbs and hindlimbs have severe reductions of the proximal limb and less severe reductions of the distal limb. Genetic and physical mapping has failed to separate the Ulnaless locus from the HoxD gene cluster (Peichel, C. L., Abbott, C. M. and Vogt, T. F. (1996) Genetics 144, 1757-1767). The Ulnaless limb phenotypes are not recapitulated by targeted mutations in any single HoxD gene, suggesting that Ulnaless may be a gain-of-function mutation in a coding sequence or a regulatory mutation. Deregulation of 5′ HoxD gene expression is observed in Ulnaless limb buds. There is ectopic expression of Hoxd-13 and Hoxd-12 in the proximal limb and reduction of Hoxd-13, Hoxd-12 and Hoxd-11 expression in the distal limb. Skeletal reductions in the proximal limb may be a consequence of posterior prevalence, whereby proximal misexpression of Hoxd-13 and Hoxd-12 results in the transcriptional and/or functional inactivation of Hox group 11 genes. The Ulnaless digit phenotypes are attributed to a reduction in the distal expression of Hoxd-13, Hoxd-12, Hoxd-11 and Hoxa-13. In addition, Hoxd-13 expression is reduced in the genital bud, consistent with the observed alterations of the Ulnaless penian bone. No alterations of HoxD expression or skeletal phenotypes were observed in the Ulnaless primary axis. We propose that the Ulnaless mutation alters a cis-acting element that regulates HoxD expression specifically in the appendicular axes of the embryo.