No abstract

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...

Abstract. Ciliary neurotrophic factor (CNTF) is expressed in high quantifies in Schwann cells of peripheral nerves during postnatal development of the rat. The absence of a hydrophobic leader sequence and the immunohistochemical localization of CNTF within the cytoplasm of these cells indicate that the factor might not be available to responsive neurons under physiological conditions. However, CNTF supports the survival of a variety of embryonic neurons, including spinal motoneurons in culture. Moreover we have recently demonstrated that the exogenous application of CNTF protein to the lesioned facial nerve of the newborn rat rescued these motoneurons from cell death. These results indicate that CNTF might indeed play a major role in assisting the survival of lesioned neurons in the adult peripheral nervous system. Here we demonstrate that the CNTF mRNA and protein levels and the manner in which they are regulated are compatible with such a function in lesioned peripheral neurons. In particular, immunohistochemical analysis showed significant quantities of CNTF at extracellular sites after sciatic nerve lesion. Western blots and determination of CNTF biological activity of the same nerve segments indicate that extracellular CNTF seems to be biologically active. After nerve lesion CNTF mRNA levels were reduced to <5 % in distal regions of the sciatic nerve whereas CNTF bioactivity decreased to only one third of the original before-lesion levels. A gradual reincrease in Schwann cells occurred concomitant with regeneration.

Abstract. Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a variety of embryonic neurons in culture. The developmental expression of CNTF occurs clearly after the time period of the physiological cell death of CNTF-responsive neurons . This, together with the sites of expression, excludes CNTF as a target-derived neuronal survival factor, at least in rodents . However, CNTF also participates in the induction of type 2 astrocyte differentiation in vitro. Here we demonstrate that the time course of the expression of CNTF-mRNA and protein:in the rat optic nerve (as evaluated by quantitative Northern blot analysis and biological activity,, respectively) is compatible with such a glial differentiation function of CNTF

SummaryWe have demonstrated that the extensive degener ation of motoneurons in the rat facial nucleus after transection of the facial nerve in newborn rats can be prevented by local ciliary neurotrophic factor (CNTF) administration. CNTF differs distinctly from known neurotrophic molecules such as NGF, BDNF and NT-3 in both its molecular characteristics (CNTF is a cytosolic rather than a secretory molecule) and its broad spectrum of biological activities.