MUSCLE-SPECIFIC CELL ABLATION CONDITIONAL UPON CRE-MEDIATED DNA RECOMBINATION IN TRANSGENIC MICE LEADS TO MASSIVE SPINAL AND CRANIAL MOTONEURON LOSS

We describe here a binary transgenic system based on Cre-mediated DNA recombination for genetic cell ablation in mice that enabled us to obt ain skeletal muscle-deficient embryos by mating two phenotypically nor mal transgenic lines. In those embryos, skeletal muscles are eliminate d as a consequence of the expression of the gene encoding the diphther ia toxin A fragment. Cell ablation occurs gradually beginning approxim ately on embryonic day (E) 12.5, and by E18.5 almost all skeletal musc le is absent. Analysis of the consequences of muscle cell ablation rev ealed that almost all spinal motoneurons are lost by E18.5, providing strong evidence that survival of spinal motoneurons during embryogenes is is dependent on signals from their target tissue, skeletal muscle, and that trophic signals produced by nonmuscle Sources are sufficient to support survival of no more than 10% of embryonic spinal motoneuron s in the absence of muscle-derived signals. There was also substantial loss of cranial (hypoglossal and facial) motoneurons in the muscle-de ficient embryos, thus indicating that cranial motoneuron survival is a lso dependent on trophic signals produced by their target tissue. Alth ough spinal motoneurons are a major target of spinal interneurons, the loss of motoneurons did not affect interneuron survival. Muscle-defic ient embryos had a cleft palate and abnormalities of the lower jaw, ra ising the possibility that they might serve as a mouse model for the h uman disorder, Robin sequence. The data reported here demonstrate the utility of a binary transgenic system for obtaining mouse embryos in w hich a specific cell population has been ablated, so that its role in embryonic development can be studied. (C) 1998 Academic Press.