A spontaneous mouse mutation, mesenchymal dysplasia (mes), is caused by a deletion of the most C-terminal cytoplasmic domain of patched (ptc)

A recessive mouse mutation, mesenchymal dysplasia (mes), which arose sponta neously on Chromosome 13, causes excess skin, increased body weight, and mi ld preaxial polydactyly. Fine gene mapping in this study indicated that mes is tightly linked to patched (ptc) that encodes a transmembrane receptor p rotein for Shh. Molecular characterization of the ptc gene of the mes mutan t and an allelism test using a ptc knockout allele (ptc(-)) demonstrated th at mes is caused by a deletion of the most C-terminal cytoplasmic domain of the ptc gene. Since mes homozygous embryos exhibit normal spinal cord deve lopment as compared with ptc- homozygotes, which die around 10 dpc with sev ere neural tube defects, the C-terminal cytoplasmic domain lost in mes muta tion is dispensable for inhibition of Shh signaling in early embryogenesis. However, compound heterozygotes of ptc- and mes alleles, which survive up to birth and die neonatally, had increased body weight and exhibited abnorm al anteroposterior axis formation of the limb buds. These findings indicate that Ptc is a negative regulator of body weight and ectopic activation of Shh signaling in the anterior mesenchyme of the limb buds, and that the C-t erminal cytoplasmic domain of Ptc is involved in its repressive action. (C) 2001 Academic Press.