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Leukemia inhibitory factor influences the timing of programmed synapses withdrawal from neonatal muscles
Y W Kwon1, S J Abbondanzo, C L Stewart
1Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Abstract:
We show that leukemia inhibitory factor (LIF) plays a physiological role in the programmed withdrawal of synapses from neonatal muscles. First, LIF mRNA is present in embryonic skeletal muscle and is developmentally 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-fold 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 myofibers. Second, treatment of the mouse tensor fascia latae (TFL), a superficial muscle of the hind leg, with LIF from birth (100 ng/day), transiently delays the withdrawal of excess inputs from polyneuronally innervated myofibers by approximately 3 days. The midpoint of the process is shifted from 7.5 +/- 10.2 +/- 0.6 days of age. LIF treatment delays synapse withdrawal by altering its timing without an appreciable effect on its rate. Third, in mice homozygous for a disruption of the 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 fiber number is unchanged in LIF null mice. Treatment with LIF does not alter the rate of neonatal growth, the number of muscle fibers in the TFL, or the reappearance of inputs that have been eliminated. Instead, LIF appears to delay maturation of the motor unit by transiently delaying the onset of synapse withdrawal. We hypothesize that this is a necessary component of a selective process that will operate simultaneously and equally on multiple, competing motor units.
Insights
Leukemia inhibitory factor (LIF) plays a key role in neonatal muscle synapse withdrawal. LIF delays this process, impacting motor unit maturation and muscle development.
Area of Science:
- Neuroscience
- Developmental Biology
- Muscle Physiology
Background:
- Synapse elimination is crucial for proper motor unit function.
- Neonatal muscle development involves programmed synapse withdrawal.
- The molecular mechanisms regulating synapse elimination are not fully understood.
Purpose of the Study:
- To investigate the role of leukemia inhibitory factor (LIF) in programmed synapse withdrawal from neonatal muscles.
- To determine the developmental regulation of LIF mRNA in skeletal muscle.
- To assess the impact of LIF manipulation on synapse elimination timing and motor unit maturation.
Main Methods:
- Quantification of LIF mRNA levels in embryonic and neonatal mouse hind leg muscles.
- Administration of LIF to neonatal mice and observation of synapse withdrawal dynamics in the tensor fascia latae (TFL) muscle.
- Analysis of synapse elimination in LIF gene-disrupted (null) mice.
- Assessment of motor unit maturation, muscle fiber number, and neonatal growth rates.
Main Results:
- LIF mRNA levels are high in embryonic muscle, decreasing significantly by birth.
- Exogenous LIF administration delays synapse withdrawal in neonatal TFL muscle by approximately 3 days.
- LIF-null mice exhibit accelerated synapse withdrawal, with the midpoint occurring 1 day earlier.
- LIF treatment does not affect muscle fiber number, neonatal growth, or the rate of synapse withdrawal.
Conclusions:
- Leukemia inhibitory factor (LIF) plays a physiological role in delaying programmed synapse withdrawal during neonatal muscle development.
- LIF appears to modulate the timing of synapse elimination, contributing to motor unit maturation.
- The findings suggest LIF is a component of a selective process regulating competing motor units.