International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


I16. Genetic Analysis of a Mouse Preaxial Polydactylous Mutant, X-linked Polydactyly (Xpl)

Yukari Yada1, 2, Shigeru Makino2, Sadao Ishiwa1, Toshihiko Shiroishi2.
1Ochanomizu Univ., Tokyo, Japan;
2
National Institute of Genetics, Mishima, Japan.

The anteroposterior axis patterning on vertebral limb morphogenesis is controlled by the formation of the zone of polarizing activity (ZPA), located at the posterior margin of the limb bud. The Sonic hedgehog (Shh) gene that is expressed at the posterior margin of limb bud is thought to mediate ZPA activity. However, regulation of the polarized expression of Shh in developing limb buds is poorly understood.

X-linked polydactyly (Xpl) is a spontaneous mouse mutation that exhibits preaxial polydactyly only on the hindfeet. To study the molecular basis of Xpl phenotype, we analyzed the expression patterns of several marker genes in the limb buds of Xpl embryos by in situ hybridization. At E11.5, ectopic expression of Shh, Fgf4, ptc, Gre and Hoxd11 were observed at the anterior margin of the hindlimb buds. These markers were not detected before the Shh gene is expressed at the posterior margin of the limb buds. Gli3 and Alx4 genes, which are expressed at the anterior region of the limb bud from earlier stage of limb development and are thought to be negative regulators of Shh, were expressed normally at E10.5 in Xpl mutant. All results suggested that, in the normal limb development, Xpl functions at the downstream of Gli3 and Alx4 signaling cascades and repress the expression of the Shh at the anterior region of the limb bud. Alternatively, Xpl may function independent of Gli3 and Alx4 pathways. In any case, mutation of Xpl gene results in the ectopic expression of Shh and formation of the extra ZPA activity, leading to the formation of the additional digits at the anterior side of the limb.

In order to isolate the Xpl gene, we carried out linkage analysis of Xpl in two crosses with MSM and KJR strains, which were established from Japanese or Korean wild mice at the National Institute of Genetics, Mishima. Because these strains have abundant polymorphic markers for the standard laboratory strains, we could take this advance and draw the detailed map. As a result, Xpl was mapped to a 0.54cM region between the microsatellite markers, DXMgc39 and DXMit32. In the human syntenic region, Xp22, a congenital face and limb deformity, Oral-facial-digital syndrome type 1 (OFD1: OMIM311200), has been mapped. Xpl is likely to be a mouse model for OFD1. Now we are constructing YAC and BAC contigs covering the critical region of Xpl gene.


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