Mouse patched1 controls body size determination and limb patterning

Hedgehog (Hh) proteins control many developmental events by inducing specif ic cell fates or regulating cell proliferation, The Patched1 (Ptc1) protein , a binding protein for Hh molecules, appears to oppose Hh signals by repre ssing transcription of genes that can be activated by Hh. Sonic hedgehog (S hh), one of the vertebrate homologs of Hh, controls patterning and growth o f the limb but the early embryonic lethality of ptc1(-/-) mice obscures the roles of ptc1 in later stages of development. We partially rescued ptc1 ho mozygous mutant embryos using a metallothionein promoter driving ptc1, In a wild-type background, the transgene causes a marked decrease in animal siz e starting during embryogenesis, and loss of anterior digits. In ptc1 homoz ygotes, a potent transgenic insert allowed survival to E14 and largely norm al morphology except for midbrain overgrowth. A less potent transgene gave rise to partially rescued embryos with massive exencephaly, and polydactyly and branched digits in the limbs. The polydactyly was preceded by unexpect ed anterior limb bud transcription of Shh, so one function of ptc1 is to re press Shh expression in the anterior limb bud.