International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I9. Analysis of Patched (ptc) Hypomorph Mutant, Mesenchymal Dysplasia (mes)

Shigeru Makino1, Yukari Yada1,2, Hiroshi Masuya1,3, Junko Ishijima1, Toshihiko Shiroishi1,3
1Mammalian Genetics, Natl. Inst. Genetics
Ochanomizu Univ.

Mesenchymal dysplasia (mes) is a recessive mouse mutant that exhibits abnormalities of mesenchyme-derived tissues, including preaxial polydactyly, shortened face, bifurcate sternum and shortened kinky tail. To identify the causative gene of mes, we carried out linkage analysis based on 241 N2 progeny generated from the cross with MSM strain derived from Japanese wild mouse. mes was mapped to a region flanked by two microsatellite markers, D13Mit 318 and D13Mit 187, where patched (ptc) has been mapped. Furthermore, we observed that mes was not genetically segregated with ptc.

To examine a possibility that ptc is the candidate for mes, we analyzed the nucleotide sequence of ptc in mes mutation. In this study, we identified a 32 bp-deletion in the C-terminal cytoplasmic domain of ptc. Ptc is a transmembrane receptor protein for a key signaling molecule Shh that is expressed in the organizing centers in developing mouse embryo, such as notochord, floor plate, ZPA of limb buds and lung. Ptc functionally antagonizes the Shh activity of cell differentiation and growth. Allelism test of mes with a ptc knockout mutant (Goodrich et al., 1996) revealed that the mice carrying both mutant alleles, mes and ptc-, exhibited severe polydactyly as well as neonatal lethality resulted from the abnormal lung development. Since neither ptc-/+ nor mes-/+ mice exhibited visible phenotype, this result indicated that mes is a hypomorphic allele for ptc, and that the cytoplasmic domain of Ptc plays an indispensable role in its antagonistic activity for Shh signaling.

The homozygotes of ptc knockout show early embryonic lethality around 10dpc and the heterozygotes exhibit only weak phenotype. These have hampered the study of ptc functions especially in later stage of development. In this study, it appeared that the compound heterozygotes of mes and ptc knockout alleles survive just after birth. Characterization of the compound heterozygotes in the later organogenesis stage demonstrated that Ptc plays important roles in the negative regulation of mesenchymal proliferation in trunk and lung, and the A-P axis formation in the limb development.

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