Motoneuron survival is enhanced in the absence of neuromuscular junction formation in embryos

Approximately half of the motoneurons produced during development die befor e birth or shortly after birth. Although it is believed that survival depen ds on a restricted supply of a trophic sustenance produced by the synaptic target tissue (i.e., muscle), it is unclear whether synapse formation per s e is involved in motoneuron survival. To address this issue, we counted cra nial motoneurons in a set of mutant mice in which formation of neuromuscula r junctions is dramatically impaired (i.e., null mutants for agrin, nerve-d erived agrin, rapsyn, and MuSK). We demonstrate that in the absence of synaptogenesis, there is an 18-34% in crease in motoneuron survival in the facial, trochlear, trigeminal motor, a nd hypoglossal nuclei; the highest survival occurred in the MuSK-deficient animals in which synapse formation is most severely compromised. There was no change in the size of the mutant motoneurons as compared with control an imals, and the morphology of the mutant motoneurons appeared normal. We pos tulate that the increased axonal branching observed in these mutants leads to a facilitated "access" of the motoneurons to muscle-derived trophic fact ors at sites other than synapses or that inactivity increases the productio n of such factors. Finally, we examined motoneurons in double mutants of CN TFR alpha (-/-) (in which there is a partial loss of motoneurons) and MuSK( -/-) (in which there is an increased survival of motoneurons). The motoneur on numbers in the double mutants parallel those of the single MuSK-deficien t mice, indicating that synapse disruption can even overcome the deleteriou s effect of CNTFR alpha ablation.