CILIARY neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitrol,2 and in vivo 3 and prevents lesion-mediated degeneration of rat motor neuron~ during early post-natal stages 4• Here we report that CNTF greatly reduces all the functional and morphological changes in pmnlpmn mice 5 , an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmnl pmn mice become apparent in the hind limbs at the end of the third post-natal week and all the mice die up to 6 or 7 weeks after birth from respirato~ ~aralysis. Treatment .with CNTF p-rolongs-survival-and greatly Imp~oves ~otor functIon of these mice. Moreover, morphological mamfestatJons, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substan-' tial degenerative changes were already present. The protective and r~storative effects of CNTF in this mouse mutant give new perspectIves for the treatment of human degenerative motor neuron diseases with CNTF.We hav~ e~aluate~ the effects of CNTF in the pmn/ pmn mouse, whIch IS an ammal model for human spinal motor neuron disease 5 . In contrast to two other mouse mutants wobbler 6 -8 and mnd 9,1O, the manifestations of motor neuron d~generation in pmn/ pmn mice appear earlier and progress more rapidly. In 4-wee~-0Id pmn/ pmn mice, the number ofaxons of the phrenic nerve IS already highly reduced, indicating that at this time the Number of phrenic nerve axonsThe brain stem of mice perfused with 4% formaldehyde was embedded in paraffin, serial sections 7 -fLm thick were stained with cresyl violet, and the nucleoli of facial motor neurons were counted in every fifth section on both sides as previously described" Counts were not corrected for spl it nucleoli 4 ,15, The mean of the counts on both sides was used for each animal. Phrenic nerves were prepared after perfusion of the animals with 4% formalin, Nerves were postfixed in 4% formalin, dehydrated, then 5-fLm transverse sections made and stained according to ref, 16, Myelinated axons were counted from photographs taken from nerve sections under the light microscope, Data shown are means ± s,e.m, for each group, ND, not determined, * Statistical significance was tested by Student's t-test, P< 0,0005, 502 disease has already reached an advanced stage. The motor neurons of pmn/ pmn mice first undergo a reduction in cell size, then chromatolysis and finally cell death, similar to the pathological changes seen in many cases of human motor neuron diseases ll. The gene defect responsible for the motor neu'ron changes in pmn/ pmn mice is still unknown. But an insufficient or defective expression of CNTF does not seem to be responsible for the degenerative changes. Northern blots of sciatic nerve reveal CNTF transcripts with similar size and intensity to those of the h...
The rat sciatic nerve originates from the spinal segments L4-L6. It is unifascicular at the trochanter; 5-7 mm distally, the nerve splits into two and then into four fascicles. The tibial portion gives rise to the tibial and the sural nerves, and the peroneal portion gives rise to the peroneal nerve and a cutaneous branch that perforates the lateral hamstring muscles to innervate the proximolateral face of the calf. The number and type of the axons in these branches were determined in light and electron micrographs of normal nerves, and after de-efferentation or sympathectomy. Deafferentation was technically not feasible because spinal ganglia and ventral roots were supplied by the same vascular plexus. The tibial nerve contained 1,000 motor and 3,500 myelinated afferent axons, 3,700 sympathetic axons, and 5,400 unmyelinated afferent axons. The peroneal nerve contained 600 motor and 1,300 myelinated afferent axons, 1,100 sympathetic axons and 3,000 unmyelinated afferent axons. The sural nerve contained 1,100 myelinated and 2,800 unmyelinated afferent axons; in addition, there were 1,500 unmyelinated sympathetic axons. The cutaneous branch consisted of 400 myelinated and 1,800 unmyelinated afferent axons. Thus, the entire sciatic nerve at midthigh is composed of about 27,000 axons; 6% are myelinated motor axons, 23% and 48% are myelinated and unmyelinated sensory axons, respectively, and 23% are unmyelinated sympathetic axons. The techniques used did not demonstrate sympathetic axons in the cutaneous branch and did not reveal the few motor axons contained in the sural nerve.
Target innervation by specific neuronal populations involves still incompletely understood interactions between central and peripheral factors. We show that glial cell line-derived neurotrophic factor (GDNF), initially characterized for its role as a survival factor, is present early in the plexus of the developing forelimb and later in two muscles: the cutaneus maximus and latissimus dorsi. In the absence of GDNF signaling, motor neurons that normally innervate these muscles are mispositioned within the spinal cord and muscle invasion by their axons is dramatically reduced. The ETS transcription factor PEA3 is normally expressed by these motor neurons and fails to be induced in most of them in GDNF signaling mutants. Thus, GDNF acts as a peripheral signal to induce PEA3 expression in specific motor neuron pools thereby regulating both cell body position and muscle innervation.
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