THE MOUSE ULNALESS MUTATION DEREGULATES POSTERIOR HOXD GENE-EXPRESSION AND ALTERS APPENDICULAR PATTERNING

The semi-dominant mouse mutation Ulnaless alters patterning of the app endicular but not the axial skeleton, Ulnaless forelimbs and hindlimbs have severe reductions of the proximal limb and less severe reduction s of the distal limb, Genetic and physical mapping has failed to separ ate the Ulnaless locus from the HoxD gene cluster (Peichel, C. L., Abb ott, C. M. and Vogt, T. F. (1996) Genetics 144, 1757-1767), The Ulnale ss limb phenotypes are not recapitulated by targeted mutations in any single HoxD gene, suggesting that Ulnaless may be a gain-of-function m utation in a coding sequence or a regulatory mutation, Deregulation of 5' HoxD gene expression is observed in Ulnaless limb buds. There is e ctopic expression of Hoxd-13 and Hoxd-12 in the proximal limb and redu ction of Hoxd-13, Hoxd-12 and Hexd-11 expression in the distal limb. S keletal reductions in the proximal limb may be a consequence of poster ior prevalence, whereby proximal misexpression of Hoxd-13 and Hoxd-12 results in the transcriptional and/or functional inactivation of Hox g roup 11 genes, The Ulnaless digit phenotypes are attributed to a reduc tion 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, consi stent with the observed alterations of the Ulnaless penian bone, No al terations of HoxD expression or skeletal phenotypes were observed in t he Ulnaless primary axis, We propose that the Ulnaless mutation alters a cis-acting element that regulates HoxD expression specifically in t he appendicular axes of the embryo.