LEUKEMIA INHIBITORY FACTOR INFLUENCES THE TIMING OF PROGRAMMED SYNAPSE WITHDRAWAL FROM NEONATAL MUSCLES

We show that leukemia inhibitory factor (LIF) plays a physiological ro le in the programmed withdrawal of synapses from neonatal muscles. Fir st, LIF mRNA is present in embryonic skeletal muscle and is developmen tally regulated. We detect high levels of LIF mRNA at embryonic day 17 (E17) in mouse hind leg muscles. The content of LIF mRNA falls 10-fol d between E17 and birth and then remains low in the neonate and adult. The decrease in LIF mRNA in skeletal muscle coincides with the end of secondary myogenesis and the completion of the adult number of myofib ers. Second, treatment of the mouse tenser fascia latae (TFL), a super ficial muscle of the hind leg, with LIF from birth (100 ng/day), trans iently delays the withdrawal of excess inputs from polyneuronally inne rvated myofibers by approximately 3 days. The midpoint of the process is shifted from 7.5 +/- 0.5 to 10.2 +/- 0.6 days of age. LIF treatment delays synapse withdrawal by altering its timing without an appreciab le effect on its rate. Third, in mice homozygous for a disruption of t he LIF gene, the midpoint in the reduction of multiply innervated TFL myofibers occurs 1 day earlier, at 6.5 +/- 0.5 days of age. Muscle fib er number is unchanged in LIF null mice. Treatment with LIF does not a lter the rate of neonatal growth, the number of muscle fibers in the T FL, or the reappearance of inputs that have been eliminated. Instead, LIF appears to delay maturation of the motor unit by transiently delay ing the onset of synapse with-drawal. We hypothesize that this is a ne cessary component of a selective process that will operate simultaneou sly and equally on multiple, competing motor units. (C) 1995 John Wile y & Sons, Inc.