Abstract
The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.
Highlights
The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested
These included decreased levels of glial cell line-derived neurotrophic factor (GDNF) compared to levels in agematched control extraocular muscles[1,2]. This was interesting in light of previous studies which demonstrated that orbital injection of GDNF in juvenile chicks or sustained GDNF treatment of a single extraocular muscle in adult rabbits resulted in altered muscle force g eneration[3,4,5]
By 2 and 5 months, the infant-associated exotropia seen in all the infant non-human primates was reduced to 1.6° and 3.5°, angles below what is defined as strabismus (Fig. 3), adding support to the data showing maintained or induced eye misalignment in the GDNF-treated infant monkeys
Summary
The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Recent gene array and quantitative PCR analyses showed that extraocular muscles obtained from adult subjects with strabismus undergoing normal resection surgery in order to improve eye alignment had significant alterations in gene expression levels and protein composition These included decreased levels of glial cell line-derived neurotrophic factor (GDNF) compared to levels in agematched control extraocular muscles[1,2]. Based on the demonstration that GDNF levels were altered in the muscles from surgical sample from individuals with strabismus, as shown by using both DNA microarray and RNA PCR a nalyses[1,2], sustained treatment of rabbits with GDNF was performed and resulted in muscles that generated decreased force compared to age-matched controls[5] Based on these results, in the present study we tested the effect of unilateral sustained delivery of GDNF to one medial rectus muscle in six infant monkeys. The number of Pitx[2] myogenic precursor cells was assessed in all the horizontal rectus muscles
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